Setting New Routes for Antifungal Drug Discovery Against Pathogenic Fungi

Kleber    S.    Freitas e Silva; Lívia       C. Silva; Relber    A.   Gonçales; Bruno    J.   Neves; Célia    M.A.   Soares; Maristela	      Pereira
doi:10.2174/1381612826666200317125956
Abstract

Fungal diseases are life-threatening to human health and responsible for millions of deaths around the world. Fungal pathogens lead to a high number of morbidity and mortality. Current antifungal treatment comprises drugs, such as azoles, echinocandins, and polyenes and the cure is not guaranteed. In addition, such drugs are related to severe side effects and the treatment lasts for an extended period. Thus, setting new routes for the discovery of effective and safe antifungal drugs should be a priority within the health care system. The discovery of alternative and efficient antifungal drugs showing fewer side effects is time-consuming and remains a challenge. Natural products can be a source of antifungals and used in combinatorial therapy. The most important natural products are antifungal peptides, antifungal lectins, antifungal plants, and fungi secondary metabolites. Several proteins, enzymes, and metabolic pathways could be targets for the discovery of efficient inhibitor compounds and recently, heat shock proteins, calcineurin, salinomycin, the trehalose biosynthetic pathway, and the glyoxylate cycle have been investigated in several fungal species. HSP protein inhibitors and echinocandins have been shown to have a fungicidal effect against azole-resistant fungi strains. Transcriptomic and proteomic approaches have advanced antifungal drug discovery and pointed to new important specific-pathogen targets. Certain enzymes, such as those from the glyoxylate cycle, have been a target of antifungal compounds in several fungi species. Natural and synthetic compounds inhibited the activity of such enzymes and reduced the ability of fungal cells to transit from mycelium to yeast, proving to be promisor antifungal agents. Finally, computational biology has developed effective approaches, setting new routes for early antifungal drug discovery since normal approaches take several years from discovery to clinical use. Thus, the development of new antifungal strategies might reduce the therapeutic time and increase the quality of life of patients.
Keywords: Antifungal, drug discovery, pathogenic fungi, natural products, new target, high-throughput.
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[1] 
Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med  2012; 4(165) 165rv13
[http://dx.doi.org/10.1126/scitranslmed.3004404] [PMID: 23253612] 
[2] 
Sanglard D, Coste A, Ferrari S. Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. FEMS Yeast Res  2009; 9(7): 1029-50.
[http://dx.doi.org/10.1111/j.1567-1364.2009.00578.x] [PMID: 19799636] 
[3] 
Benitez LL, Carver PL. Adverse effects associated with long-term administration of azole antifungal agents. Drugs  2019; 79(8): 833-53.
[http://dx.doi.org/10.1007/s40265-019-01127-8] [PMID: 31093949] 
[4] 
Zheng Y-H, Ma Y-Y, Ding Y, Chen X-Q, Gao G-X. An insight into new strategies to combat antifungal drug resistance. Drug Des Devel Ther  2018; 12: 3807-16.
[http://dx.doi.org/10.2147/DDDT.S185833] [PMID: 30464412] 
[5] 
Revie NM, Iyer KR, Robbins N, Cowen LE. Antifungal drug resistance: evolution, mechanisms and impact. Curr Opin Microbiol  2018; 45: 70-6.
[http://dx.doi.org/10.1016/j.mib.2018.02.005] [PMID: 29547801] 
[6] 
Costa-Orlandi CB, Sardi JCO, Pitangui NS, et al. Fungal biofilms and polymicrobial diseases. J Fungi (Basel) Internet  2017; 3(2) E22Available at:. https://www.ncbi.nlm.nih.gov/ pmc/articles/ PMC5715925/ http://dx.doi.org/10.3390/jof3020022
[PMID: 29371540] 
[7] 
Nami S, Aghebati-Maleki A, Morovati H, Aghebati-Maleki L. Current antifungal drugs and immunotherapeutic approaches as promising strategies to treatment of fungal diseases. Biomed Pharmacother  2019; 110: 857-68.
[http://dx.doi.org/10.1016/j.biopha.2018.12.009] [PMID: 30557835] 
[8] 
Teodoro GR, Ellepola K, Seneviratne CJ, Koga-Ito CY. Potential use of phenolic acids as anti-candida agents: a review. Front Microbiol Internet  2015; 6: 1420.Available at:. https://www.frontiersin.org/ articles/10.3389/fmicb.2015.01420/full
[http://dx.doi.org/10.3389/fmicb.2015.01420] [PMID:  26733965] 
[9] 
Prado RS, Alves RJ, Oliveira CM, et al. Inhibition of Paracoccidioides lutzii Pb01 isocitrate lyase by the natural compound argentilactone and its semi-synthetic derivatives. PLoS One  2014; 9(4) e94832
[http://dx.doi.org/10.1371/journal.pone.0094832] [PMID: 24752170] 
[10] 
Mickymaray S, Alturaiki W. Antifungal efficacy of marine macroalgae against fungal isolates from bronchial asthmatic cases. Molecules  2018; 23(11) E3032
[http://dx.doi.org/10.3390/molecules23113032] [PMID: 30463364] 
[11] 
Xu L, Meng W, Cao C, Wang J, Shan W, Wang Q. Antibacterial and antifungal compounds from marine fungi. Mar Drugs  2015; 13(6): 3479-513.
[http://dx.doi.org/10.3390/md13063479] [PMID: 26042616] 
[12] 
Araújo FS, Coelho LM, Silva LdoC, et al. Effects of argentilactone on the transcriptional profile, cell wall and oxidative stress of Paracoccidioides spp. PLoS Negl Trop Dis  2016; 10(1) e0004309
[http://dx.doi.org/10.1371/journal.pntd.0004309] [PMID: 26734764] 
[13] 
E Silva KS, da S Neto BR, Zambuzzi-Carvalho PF, et al. Response of Paracoccidioides lutzii to the antifungal camphene thiosemicarbazide determined by proteomic analysis. Future Microbiol  2018; 13: 1473-96.
[http://dx.doi.org/10.2217/fmb-2018-0176] [PMID: 30311782] 
[14] 
E Silva KSF, Lima RM, Baeza LC, et al. Interactome of glyceraldehyde-3-phosphate dehydrogenase points to the existence of metabolons in Paracoccidioides lutzii. Front Microbiol  2019; 10: 1537.
[http://dx.doi.org/10.3389/fmicb.2019.01537] [PMID: 31338083] 
[15] 
Halouska S, Fenton RJ, Barletta RG, Powers R. Predicting the in vivo mechanism of action for drug leads using NMR metabolomics. ACS Chem Biol  2012; 7(1): 166-71.
[http://dx.doi.org/10.1021/cb200348m] [PMID: 22007661] 
[16] 
Roemer T, Krysan DJ. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med  2014; 4(5): a019703-3.
[http://dx.doi.org/10.1101/cshperspect.a019703] [PMID: 24789878] 
[17] 
Butler MS, Buss AD. Natural products--the future scaffolds for novel antibiotics? Biochem Pharmacol  2006; 71(7): 919-29.
[http://dx.doi.org/10.1016/j.bcp.2005.10.012] [PMID: 16289393] 
[18] 
Mahlapuu M, Håkansson J, Ringstad L, Björn C. Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front Cell Infect Microbiol  2016; 6: 194.
[http://dx.doi.org/10.3389/fcimb.2016.00194] [PMID: 28083516] 
[19] 
Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol  2005; 3(3): 238-50.
[http://dx.doi.org/10.1038/nrmicro1098] [PMID: 15703760] 
[20] 
Aerts AM, François IEJA, Meert EMK, Li Q-T, Cammue BPA, Thevissen K. The antifungal activity of RsAFP2, a plant defensin from raphanus sativus, involves the induction of reactive oxygen species in Candida albicans. J Mol Microbiol Biotechnol  2007; 13(4): 243-7.
[http://dx.doi.org/10.1159/000104753] [PMID: 17827975] 
[21] 
Lobo DS, Pereira IB, Fragel-Madeira L, et al. Antifungal Pisum sativum defensin 1 interacts with Neurospora crassa cyclin F related to the cell cycle. Biochemistry  2007; 46(4): 987-96.
[http://dx.doi.org/10.1021/bi061441j] [PMID: 17240982] 
[22] 
Nicolas P. Multifunctional host defense peptides: intracellular-targeting antimicrobial peptides. FEBS J  2009; 276(22): 6483-96.
[http://dx.doi.org/10.1111/j.1742-4658.2009.07359.x] [PMID: 19817856] 
[23] 
Mizoguchi J, Saito T, Mizuno K, Hayano K. On the mode of action of a new antifungal antibiotic, aculeacin A: inhibition of cell wall synthesis in Saccharomyces cerevisiae. J Antibiot (Tokyo)  1977; 30(4): 308-13.
[http://dx.doi.org/10.7164/antibiotics.30.308] [PMID: 324960] 
[24] 
Chapman T, Kinsman O, Houston J. Chitin biosynthesis in Candida albicans grown in vitro and in vivo and its inhibition by nikkomycin Z. Antimicrob Agents Chemother  1992; 36(9): 1909-14.
[http://dx.doi.org/10.1128/AAC.36.9.1909] [PMID: 1416881] 
[25] 
Ciociola T, Giovati L, Conti S, Magliani W, Santinoli C, Polonelli L. Natural and synthetic peptides with antifungal activity. Future Med Chem  2016; 8(12): 1413-33.
[http://dx.doi.org/10.4155/fmc-2016-0035] [PMID: 27502155] 
[26] 
Matejuk A, Leng Q, Begum MD, et al. Peptide-based antifungal therapies against emerging infections. Drugs Future  2010; 35(3): 197.
[http://dx.doi.org/10.1358/dof.2010.035.03.1452077] [PMID: 20495663] 
[27] 
Bondaryk M, Staniszewska M, Zielińska P, Urbańczyk-Lipkowska Z. Natural antimicrobial peptides as inspiration for design of a new generation antifungal compounds. J Fungi (Basel)  2017; 3(3): 46.
[http://dx.doi.org/10.3390/jof3030046] [PMID: 29371563] 
[28] 
Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res  2016; 44(D1): D1087-93.
[http://dx.doi.org/10.1093/nar/gkv1278] [PMID: 26602694] 
[29] 
Di Luca M, Maccari G, Maisetta G, Batoni G. BaAMPs: the database of biofilm-active antimicrobial peptides. Biofouling  2015; 31(2): 193-9.
[http://dx.doi.org/10.1080/08927014.2015.1021340] [PMID: 25760404] 
[30] 
Thevissen K, de Mello Tavares P, Xu D, et al. The plant defensin RsAFP2 induces cell wall stress, septin mislocalization and accumulation of ceramides in Candida albicans. Mol Microbiol  2012; 84(1): 166-80.
[http://dx.doi.org/10.1111/j.1365-2958.2012.08017.x] [PMID: 22384976] 
[31] 
Vriens K, Cools TL, Harvey PJ, et al. The radish defensins RsAFP1 and RsAFP2 act synergistically with caspofungin against Candida albicans biofilms. Peptides  2016; 75: 71-9.
[http://dx.doi.org/10.1016/j.peptides.2015.11.001] [PMID: 26592804] 
[32] 
De Samblanx GW, Goderis IJ, Thevissen K, et al. Mutational analysis of a plant defensin from radish (Raphanus sativus L.) reveals two adjacent sites important for antifungal activity. J Biol Chem  1997; 272(2): 1171-9.
[http://dx.doi.org/10.1074/jbc.272.2.1171] [PMID: 8995418] 
[33] 
Barbosa FM, Daffre S, Maldonado RA, Miranda A, Nimrichter L, Rodrigues ML. Gomesin, a peptide produced by the spider Acanthoscurria gomesiana, is a potent anticryptococcal agent that acts in synergism with fluconazole. FEMS Microbiol Lett  2007; 274(2): 279-86.
[http://dx.doi.org/10.1111/j.1574-6968.2007.00850.x] [PMID: 17645524] 
[34] 
Machado A, Fázio MA, Miranda A, Daffre S, Machini MT. Synthesis and properties of cyclic gomesin and analogues. J Pept Sci  2012; 18(9): 588-98.
[http://dx.doi.org/10.1002/psc.2439] [PMID: 22865764] 
[35] 
Domingues TM, Perez KR, Miranda A, Riske KA. Comparative study of the mechanism of action of the antimicrobial peptide gomesin and its linear analogue: The role of the β-hairpin structure. Biochim Biophys Acta  2015; 1848(10 Pt A): 2414-21.
[http://dx.doi.org/10.1016/j.bbamem.2015.07.012] [PMID: 26231588] 
[36] 
Hector RF, Zimmer BL, Pappagianis D. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob Agents Chemother  1990; 34(4): 587-93.
[http://dx.doi.org/10.1128/AAC.34.4.587] [PMID: 2344165] 
[37] 
Clemons KV, Stevens DA. Efficacy of nikkomycin Z against experimental pulmonary blastomycosis. Antimicrob Agents Chemother  1997; 41(9): 2026-8.
[http://dx.doi.org/10.1128/AAC.41.9.2026] [PMID: 9303408] 
[38] 
Li RK, Rinaldi MG. In vitro antifungal activity of nikkomycin Z in combination with fluconazole or itraconazole. Antimicrob Agents Chemother  1999; 43(6): 1401-5.
[http://dx.doi.org/10.1128/AAC.43.6.1401] [PMID: 10348760] 
[39] 
Sandovsky-Losica H, Shwartzman R, Lahat Y, Segal E. Antifungal activity against Candida albicans of nikkomycin Z in combination with caspofungin, voriconazole or amphotericin B. J Antimicrob Chemother  2008; 62(3): 635-7.
[http://dx.doi.org/10.1093/jac/dkn216] [PMID: 18490373] 
[40] 
Kovács R, Nagy F, Tóth Z, Bozó A, Balázs B, Majoros L. Synergistic effect of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms. Lett Appl Microbiol  2019; 69(4): 271-8.
[http://dx.doi.org/10.1111/lam.13204] [PMID: 31385615] 
[41] 
Xu X, Lai R. The chemistry and biological activities of peptides from amphibian skin secretions. Chem Rev  2015; 115(4): 1760-846.
[http://dx.doi.org/10.1021/cr4006704] [PMID: 25594509] 
[42] 
Mor A, Hani K, Nicolas P. The vertebrate peptide antibiotics dermaseptins have overlapping structural features but target specific microorganisms. J Biol Chem  1994; 269(50): 31635-41.
[PMID: 7989335] 
[43] 
Giacometti A, Cirioni O, Barchiesi F, Del Prete MS, Scalise G. Antimicrobial activity of polycationic peptides. Peptides  1999; 20(11): 1265-73.
[http://dx.doi.org/10.1016/S0196-9781(99)00131-X] [PMID: 10612440] 
[44] 
Leite JRSA, Brand GD, Silva LP, et al. Dermaseptins from Phyllomedusa oreades and Phyllomedusa distincta: Secondary structure, antimicrobial activity, and mammalian cell toxicity. Comp Biochem Physiol A Mol Integr Physiol  2008; 151(3): 336-43.
[http://dx.doi.org/10.1016/j.cbpa.2007.03.016] [PMID: 17442605] 
[45] 
Pál T, Abraham B, Sonnevend A, Jumaa P, Conlon JM. Brevinin-1BYa: a naturally occurring peptide from frog skin with broad-spectrum antibacterial and antifungal properties. Int J Antimicrob Agents  2006; 27(6): 525-9.
[http://dx.doi.org/10.1016/j.ijantimicag.2006.01.010] [PMID: 16713189] 
[46] 
Youssef DT, Shaala LA, Mohamed GA, Badr JM, Bamanie FH, Ibrahim SR. Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei. Mar Drugs  2014; 12(4): 1911-23.
[http://dx.doi.org/10.3390/md12041911] [PMID: 24694570] 
[47] 
Clark DP, Carroll J, Naylor S, Crews P. An antifungal cyclodepsipeptide, cyclolithistide a, from the sponge Theonella swinhoei. J Org Chem  1998; 63(24): 8757-64.
[http://dx.doi.org/10.1021/jo980758p] 
[48] 
Bae M, Kim H, Moon K, et al. Mohangamides A and B, new dilactone-tethered pseudo-dimeric peptides inhibiting Candida albicans isocitrate lyase. Org Lett  2015; 17(3): 712-5.
[http://dx.doi.org/10.1021/ol5037248] [PMID: 25622093] 
[49] 
Del Rio M, de la Canal L, Regente M. Plant antifungal lectins: Mechanism of action and targets on human pathogenic fungi. CPPS 2019;20 Available from:. http://www.eurekaselect.com/ 174773/ article
[50] 
Gomes Filho SM, Cardoso JD, Anaya K, et al. Marine sponge lectins: actual status on properties and biological activities. Molecules  2014; 20(1): 348-57.
[http://dx.doi.org/10.3390/molecules20010348] [PMID: 25549059] 
[51] 
Singh RS, Thakur SR, Bansal P. Algal lectins as promising biomolecules for biomedical research. Crit Rev Microbiol  2015; 41(1): 77-88.
[http://dx.doi.org/10.3109/1040841X.2013.798780] [PMID: 23855360] 
[52] 
Gardères J, Bourguet-Kondracki M-L, Hamer B, Batel R, Schröder HC, Müller WE. Porifera lectins: diversity, physiological roles and biotechnological potential. Mar Drugs  2015; 13(8): 5059-101.
[http://dx.doi.org/10.3390/md13085059] [PMID: 26262628] 
[53] 
Kobayashi Y, Kawagishi H. Fungal lectins: a growing family. In: Lectins  Hirabayashi J. Springer New York, New York, NY; 15-38.(2014); Available from:. http://link.springer.com/1 0.1007/ 978-1-4939-1292-6_2 
[54] 
Breitenbach Barroso Coelho LC, Marcelino Dos Santos Silva P, Felix de Oliveira W, et al. Lectins as antimicrobial agents. J Appl Microbiol  2018; 125(5): 1238-52.
[http://dx.doi.org/10.1111/jam.14055] [PMID: 30053345] 
[55] 
Mukherjee S, Zheng H, Derebe MG, et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature  2014; 505(7481): 103-7.
[http://dx.doi.org/10.1038/nature12729] [PMID: 24256734] 
[56] 
Coelho LCBB, Silva PM dos S, Lima VL de M, et al. Lectins, interconnecting proteins with biotechnological/pharmacological and therapeutic applications. Evid Based Complement Alternat Med  2017; 2017 1594074
[http://dx.doi.org/10.1155/2017/1594074] [PMID: 28367220] 
[57] 
Jones TH, McClelland EE, McFeeters H, McFeeters RL. Novel antifungal activity for the lectin scytovirin: inhibition of Cryptococcus neoformans and Cryptococcus gattii. Front Microbiol  2017; 8: 755.
[http://dx.doi.org/10.3389/fmicb.2017.00755] [PMID: 28536555] 
[58] 
Procópio TF, de Siqueira Patriota LL, de Moura MC, et al. CasuL: A new lectin isolated from Calliandra surinamensis leaf pinnulae with cytotoxicity to cancer cells, antimicrobial activity and antibiofilm effect. Int J Biol Macromol  2017; 98: 419-29.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.02.019] [PMID: 28174088] 
[59] 
Regente M, Taveira GB, Pinedo M, et al. A sunflower lectin with antifungal properties and putative medical mycology applications. Curr Microbiol  2014; 69(1): 88-95.
[http://dx.doi.org/10.1007/s00284-014-0558-z] [PMID: 24623187] 
[60] 
Ruas LP, Bernardes ES, Fermino ML, et al. Lack of galectin-3 drives response to Paracoccidioides brasiliensis toward a Th2-biased immunity. PLoS One  2009; 4(2) e4519
[http://dx.doi.org/10.1371/journal.pone.0004519] [PMID: 19229338] 
[61] 
Linden JR, De Paepe ME, Laforce-Nesbitt SS, Bliss JM. Galectin-3 plays an important role in protection against disseminated candidiasis. Med Mycol  2013; 51(6): 641-51.
[http://dx.doi.org/10.3109/13693786.2013.770607] [PMID: 23488971] 
[62] 
Wu S-Y, Yu J-S, Liu F-T, Miaw S-C, Wu-Hsieh BA. Galectin-3 negatively regulates dendritic cell production of il-23/il-17–axis cytokines in infection by Histoplasma capsulatum. JI  2013; 190(7): 3427-7.
[63] 
Simões CMO, Schenke EP, Gosmann G, Mello JCP, Mentz LA, Petrovick PR. Farmacognosia: da planta ao medicamento.  6th ed.  1999.
[64] 
Zabka M, Pavela R. Antifungal efficacy of some natural phenolic compounds against significant pathogenic and toxinogenic filamentous fungi. Chemosphere  2013; 93(6): 1051-6.
[http://dx.doi.org/10.1016/j.chemosphere.2013.05.076] [PMID: 23800587] 
[65] 
Fernández LR, Butassi E, Svetaz L, Zacchino SA, Palermo JA, Sánchez M. Antifungal terpenoids from Hyalis argentea var. latisquama. J Nat Prod  2014; 77(7): 1579-85.
[http://dx.doi.org/10.1021/np500032u] [PMID: 25026191] 
[66] 
de Freitas CS, Kato L, de Oliveira CM, et al. β-Carboline alkaloids from Galianthe ramosa inhibit malate synthase from Paracoccidioides spp. Planta Med  2014; 80(18): 1746-52.
[http://dx.doi.org/10.1055/s-0034-1383305] [PMID: 25412318] 
[67] 
Costa FG, Neto BR da S, Gonçalves RL, et al. Alkaloids as inhibitors of malate synthase from Paracoccidioides spp.: receptor-ligand interaction-based virtual screening and molecular docking studies, antifungal activity, and the adhesion process. Antimicrob Agents Chemother  2015; 59(9): 5581-94.
[http://dx.doi.org/10.1128/AAC.04711-14] [PMID: 26124176] 
[68] 
Agarwal AK, Xu T, Jacob MR, et al. Role of heme in the antifungal activity of the azaoxoaporphine alkaloid sampangine. Eukaryot Cell  2008; 7(2): 387-400.
[http://dx.doi.org/10.1128/EC.00323-07] [PMID: 18156292] 
[69] 
Sharma N, Tripathi A. Effects of Citrus sinensis (L.) Osbeck epicarp essential oil on growth and morphogenesis of Aspergillus niger (L.) Van Tieghem. Microbiol Res  2008; 163(3): 337-44.
[http://dx.doi.org/10.1016/j.micres.2006.06.009] [PMID: 16870411] 
[70] 
Furletti VF, Teixeira IP, Obando-Pereda G, et al. Action of Coriandrum sativum L. Essential oil upon oral Candida albicans biofilm formation. Evid Based Complement Alternat Med  2011; 2011 985832
[http://dx.doi.org/10.1155/2011/985832] [PMID: 21660258] 
[71] 
Wu XZ, Cheng AX, Sun LM, Lou HX. Effect of plagiochin E, an antifungal macrocyclic bis(bibenzyl), on cell wall chitin synthesis in Candida albicans. Acta Pharmacol Sin  2008; 29(12): 1478-85.
[http://dx.doi.org/10.1111/j.1745-7254.2008.00900.x] [PMID: 19026167] 
[72] 
Ahmad A, Khan A, Kumar P, Bhatt RP, Manzoor N. Antifungal activity of Coriaria nepalensis essential oil by disrupting ergosterol biosynthesis and membrane integrity against Candida. Yeast  2011; 28(8): 611-7.
[http://dx.doi.org/10.1002/yea.1890] [PMID: 21755533] 
[73] 
Ayaz M, Ullah F, Sadiq A, et al. Synergistic interactions of phytochemicals with antimicrobial agents: Potential strategy to counteract drug resistance. Chem Biol Interact  2019; 308: 294-303.
[http://dx.doi.org/10.1016/j.cbi.2019.05.050] [PMID: 31158333] 
[74] 
Singh S, Fatima Z, Ahmad K, Hameed S. Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism. PLoS One  2018; 13(8) e0203079
[http://dx.doi.org/10.1371/journal.pone.0203079] [PMID: 30157240] 
[75] 
Khan SN, Khan S, Misba L, Sharief M, Hashmi A, Khan AU. Synergistic fungicidal activity with low doses of eugenol and amphotericin B against Candida albicans. Biochem Biophys Res Commun  2019; 518(3): 459-64.
[http://dx.doi.org/10.1016/j.bbrc.2019.08.053] [PMID: 31443962] 
[76] 
Sangalli-Leite F, Scorzoni L, Alves de Paula E Silva AC, et al. Synergistic effect of pedalitin and amphotericin B against Cryptococcus neoformans by in vitro and in vivo evaluation. Int J Antimicrob Agents  2016; 48(5): 504-11.
[http://dx.doi.org/10.1016/j.ijantimicag.2016.07.025] [PMID: 27742203] 
[77] 
Pasrija R, Kundu D. Interaction of curcumin with azoles and polyenes against aspergillus infections. RJLBPCS  2018; 4(4): 271-9.
[78] 
Hwang E-I, Yun B-S, Kim Y-K, et al. Phellinsin A, a novel chitin synthases inhibitor produced by Phellinus sp. PL3. J Antibiot (Tokyo)  2000; 53(9): 903-11.
[http://dx.doi.org/10.7164/antibiotics.53.903] [PMID: 11099223] 
[79] 
Hwang E-I, Yun B-S, Kim Y-K, et al. Chaetoatrosin A, a novel chitin synthase II inhibitor produced by Chaetomium atrobrunneum F449. J Antibiot (Tokyo)  2000; 53(3): 248-55.
[http://dx.doi.org/10.7164/antibiotics.53.248] [PMID: 10819295] 
[80] 
Wu B, Oesker V, Wiese J, Schmaljohann R, Imhoff JF. Two new antibiotic pyridones produced by a marine fungus, Trichoderma sp. strain MF106. Mar Drugs  2014; 12(3): 1208-19.
[http://dx.doi.org/10.3390/md12031208] [PMID: 24663111] 
[81] 
Haga A, Tamoto H, Ishino M, et al. Pyridone alkaloids from a marine-derived fungus, Stagonosporopsis cucurbitacearum, and their activities against azole-resistant Candida albicans. J Nat Prod  2013; 76(4): 750-4.
[http://dx.doi.org/10.1021/np300876t] [PMID: 23496341] 
[82] 
Li J, Buchner J. Structure, function and regulation of the hsp90 machinery. Biomed J  2013; 36(3): 106-17.
[http://dx.doi.org/10.4103/2319-4170.113230] [PMID: 23806880] 
[83] 
Leach MD, Klipp E, Cowen LE, Brown AJP. Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs. Nat Rev Microbiol  2012; 10(10): 693-704.
[http://dx.doi.org/10.1038/nrmicro2875] [PMID: 22976491] 
[84] 
Donlin LT, Andresen C, Just S, et al. Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes Dev  2012; 26(2): 114-9.
[http://dx.doi.org/10.1101/gad.177758.111] [PMID: 22241783] 
[85] 
Cowen LE, Singh SD, Köhler JR, et al. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci USA  2009; 106(8): 2818-23.
[http://dx.doi.org/10.1073/pnas.0813394106] [PMID: 19196973] 
[86] 
Singh-Babak SD, Babak T, Diezmann S, et al. Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog  2012; 8(5) e1002718
[http://dx.doi.org/10.1371/journal.ppat.1002718] [PMID: 22615574] 
[87] 
Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ. In vitro activity of calcineurin and heat shock protein 90 Inhibitors against Aspergillus fumigatus azole- and echinocandin-resistant strains. Antimicrob Agents Chemother  2013; 57(2): 1035-9.
[http://dx.doi.org/10.1128/AAC.01857-12] [PMID: 23165466] 
[88] 
Juvvadi PR, Lamoth F, Steinbach WJ. Calcineurin as a multifunctional regulator: unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis. Fungal Biol Rev  2014; 28(2-3): 56-69.
[http://dx.doi.org/10.1016/j.fbr.2014.02.004] [PMID: 25383089] 
[89] 
da Silva Ferreira ME, Heinekamp T, Härtl A, et al. Functional characterization of the Aspergillus fumigatus calcineurin. Fungal Genet Biol  2007; 44(3): 219-30.
[http://dx.doi.org/10.1016/j.fgb.2006.08.004] [PMID: 16990036] 
[90] 
Chen Y-L, Lehman VN, Lewit Y, Averette AF, Heitman J. Calcineurin governs thermotolerance and virulence of Cryptococcus gattii. G3 (Bethesda)  2013; 3(3): 527-39.
[http://dx.doi.org/10.1534/g3.112.004242] [PMID: 23450261] 
[91] 
Chen Y-L, Brand A, Morrison EL, et al. Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. Eukaryot Cell  2011; 10(6): 803-19.
[http://dx.doi.org/10.1128/EC.00310-10] [PMID: 21531874] 
[92] 
Maesaki S, Marichal P, Hossain MA, Sanglard D, Vanden Bossche H, Kohno S. Synergic effects of tactolimus and azole antifungal agents against azole-resistant Candida albican strains. J Antimicrob Chemother  1998; 42(6): 747-53.
[http://dx.doi.org/10.1093/jac/42.6.747] [PMID: 10052898] 
[93] 
Thevelein JM, Hohmann S. Trehalose synthase: guard to the gate of glycolysis in yeast? Trends Biochem Sci  1995; 20(1): 3-10.
[http://dx.doi.org/10.1016/S0968-0004(00)88938-0] [PMID: 7878741] 
[94] 
Elbein AD, Pan YT, Pastuszak I, Carroll D. New insights on trehalose: a multifunctional molecule. Glycobiology  2003; 13(4): 17R-27R.
[http://dx.doi.org/10.1093/glycob/cwg047] [PMID: 12626396] 
[95] 
Huczyński A. Polyether ionophores-promising bioactive molecules for cancer therapy. Bioorg Med Chem Lett  2012; 22(23): 7002-10.
[http://dx.doi.org/10.1016/j.bmcl.2012.09.046] [PMID: 23063400] 
[96] 
Antoszczak M, Huczyński A. Salinomycin and its derivatives - A new class of multiple-targeted “magic bullets”. Eur J Med Chem  2019; 176: 208-27.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.031] [PMID: 31103901] 
[97] 
Ogita A, Konishi Y, Borjihan B, Fujita K, Tanaka T. Synergistic fungicidal activities of polymyxin B and ionophores, and their dependence on direct disruptive action of polymyxin B on fungal vacuole. J Antibiot (Tokyo)  2009; 62(2): 81-7.
[http://dx.doi.org/10.1038/ja.2008.13] [PMID: 19132057] 
[98] 
Ng TS, Chew SY, Rangasamy P, et al. SNF3 as High affinity glucose sensor and its function in supporting the viability of Candida glabrata under glucose-limited environment. Front Microbiol  2015; 6: 1334.
[http://dx.doi.org/10.3389/fmicb.2015.01334] [PMID: 26648919] 
[99] 
Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell  2004; 3(5): 1076-87.
[http://dx.doi.org/10.1128/EC.3.5.1076-1087.2004] [PMID: 15470236] 
[100] 
Kaur R, Ma B, Cormack BP. A family of glycosylphosphatidylinositol-linked aspartyl proteases is required for virulence of Candida glabrata. Proc Natl Acad Sci USA  2007; 104(18): 7628-33.
[http://dx.doi.org/10.1073/pnas.0611195104] [PMID: 17456602] 
[101] 
Chew SY, Ho KL, Cheah YK, et al. Glyoxylate cycle gene ICL1 is essential for the metabolic flexibility and virulence of Candida glabrata. Sci Rep  2019; 9(1): 2843.
[http://dx.doi.org/10.1038/s41598-019-39117-1] [PMID: 30808979] 
[102] 
Ishola OA, Ting SY, Tabana YM, et al. The role of isocitrate lyase (ICL1) in the metabolic adaptation of Candida albicans biofilms. Jundishapur J Microbiol Internet  2016; 9(9) e38031
[http://dx.doi.org/10.5812/jjm.38031] [PMID: 27800147] 
[103] 
Macedo PM, Almeida-Paes R, Almeida MA, et al. Paracoccidioidomycosis due to Paracoccidioides brasiliensis S1 plus HIV co-infection. Mem Inst Oswaldo Cruz  2018; 113(3): 167-72.
[http://dx.doi.org/10.1590/0074-02760170310] [PMID: 29412355] 
[104] 
Carbonell LM, Kanetsuna F, Gil F. Chemical morphology of glucan and chitin in the cell wall of the yeast phase of Paracoccidioides brasiliensis. J Bacteriol  1970; 101(2): 636-42.
[http://dx.doi.org/10.1128/JB.101.2.636-642.1970] [PMID: 5413832] 
[105] 
Kanetsuna F, Carbonell LM. Cell wall glucans of the yeast and mycelial forms of Paracoccidioides brasiliensis. J Bacteriol  1970; 101(3): 675-80.
[http://dx.doi.org/10.1128/JB.101.3.675-680.1970] [PMID: 5442818] 
[106] 
Puccia R, Vallejo MC, Matsuo AL, Longo LVG. The paracoccidioides cell wall: past and present layers toward understanding interaction with the host. Front Microbiol Internet   2011; 2: 257.
[http://dx.doi.org/10.3389/fmicb.2011.00257] [PMID: 22194733] 
[107] 
Longo LVG, Nakayasu ES, Gazos-Lopes F, et al. Characterization of cell wall lipids from the pathogenic phase of Paracoccidioides brasiliensis cultivated in the presence or absence of human plasma. PLoS One  2013; 8(5) e63372
[http://dx.doi.org/10.1371/journal.pone.0063372] [PMID: 23691038] 
[108] 
Bowman SM, Free SJ. The structure and synthesis of the fungal cell wall. BioEssays  2006; 28(8): 799-808.
[http://dx.doi.org/10.1002/bies.20441] [PMID: 16927300] 
[109] 
Odds FC, Brown AJP, Gow NAR. Antifungal agents: mechanisms of action. Trends Microbiol  2003; 11(6): 272-9.
[http://dx.doi.org/10.1016/S0966-842X(03)00117-3] [PMID: 12823944] 
[110] 
Song JC, Stevens DA. Caspofungin: Pharmacodynamics, pharmacokinetics, clinical uses and treatment outcomes. Crit Rev Microbiol  2016; 42(5): 813-46.
[http://dx.doi.org/10.3109/1040841X.2015.1068271] [PMID: 26369708] 
[111] 
Kathiravan MK, Salake AB, Chothe AS, et al. The biology and chemistry of antifungal agents: a review. Bioorg Med Chem  2012; 20(19): 5678-98.
[http://dx.doi.org/10.1016/j.bmc.2012.04.045] [PMID: 22902032] 
[112] 
Pfaller M, Riley J, Koerner T. Effects of cilofungin (LY121019) on carbohydrate and sterol composition of Candida albicans. Eur J Clin Microbiol Infect Dis  1989; 8(12): 1067-70.
[http://dx.doi.org/10.1007/BF01975172] [PMID: 2695329] 
[113] 
Hasim S, Coleman JJ. Targeting the fungal cell wall: current therapies and implications for development of alternative antifungal agents. Future Med Chem  2019; 11(8): 869-83.
[http://dx.doi.org/10.4155/fmc-2018-0465] [PMID: 30994368] 
[114] 
Tariq VN, Devlin PL. Sensitivity of fungi to nikkomycin Z. Fungal Genet Biol  1996; 20(1): 4-11.
[http://dx.doi.org/10.1006/fgbi.1996.0003] [PMID: 8634944] 
[115] 
Walker LA, Gow NAR, Munro CA. Fungal echinocandin resistance. Fungal Genet Biol  2010; 47(2): 117-26.
[http://dx.doi.org/10.1016/j.fgb.2009.09.003] [PMID: 19770064] 
[116] 
Guo X-L, Leng P, Yang Y, Yu L-G, Lou H-X. Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump. J Appl Microbiol  2008; 104(3): 831-8.
[http://dx.doi.org/10.1111/j.1365-2672.2007.03617.x] [PMID: 18194250] 
[117] 
Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol  2007; 25(27): 4293-7.
[http://dx.doi.org/10.1200/JCO.2007.11.4207] [PMID: 17709797] 
[118] 
Geddes JMH, Caza M, Croll D, Stoynov N, Foster LJ, Kronstad JW. Analysis of the protein kinase a-regulated proteome of cryptococcus neoformans identifies a role for the ubiquitin-proteasome pathway in capsule formation. MBio  2016; 7(1): e01862-15.
[http://dx.doi.org/10.1128/mBio.01862-15] [PMID: 26758180] 
[119] 
Mayer FL, Sánchez-León E, Kronstad JW. A chemical genetic screen reveals a role for proteostasis in capsule and biofilm formation by Cryptococcus neoformans. Microb Cell  2018; 5(11): 495-510.
[http://dx.doi.org/10.15698/mic2018.11.656] [PMID: 30483521] 
[120] 
Juvvadi PR, Lee SC, Heitman J, Steinbach WJ. Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach. Virulence  2017; 8(2): 186-97.
[http://dx.doi.org/10.1080/21505594.2016.1201250] [PMID: 27325145] 
[121] 
Park H-S, Chow EWL, Fu C, et al. Calcineurin targets involved in stress survival and fungal virulence. PLoS Pathog  2016; 12(9) e1005873
[http://dx.doi.org/10.1371/journal.ppat.1005873] [PMID: 27611567] 
[122] 
Lee Y, Lee K-T, Lee SJ, et al. In Vitro and in vivo assessment of fk506 analogs as novel antifungal drug candidates. Antimicrob Agents Chemother  2018; 62(11): e01627-18.
[http://dx.doi.org/10.1128/AAC.01627-18] [PMID: 30181374] 
[123] 
Gautam P, Upadhyay SK, Hassan W, et al. Transcriptomic and proteomic profile of Aspergillus fumigatus on exposure to artemisinin. Mycopathologia  2011; 172(5): 331-46.
[http://dx.doi.org/10.1007/s11046-011-9445-3] [PMID: 21755315] 
[124] 
Singh S, Gupta S, Singh B, Sharma SK, Gupta VK, Sharma GL. Proteomic characterization of Aspergillus fumigatus treated with an antifungal coumarin for identification of novel target molecules of key pathways. J Proteome Res  2012; 11(6): 3259-68.
[http://dx.doi.org/10.1021/pr300006j] [PMID: 22533410] 
[125] 
Cagas SE, Jain MR, Li H, Perlin DS. Profiling the Aspergillus fumigatus proteome in response to caspofungin. Antimicrob Agents Chemother  2011; 55(1): 146-54.
[http://dx.doi.org/10.1128/AAC.00884-10] [PMID: 20974863] 
[126] 
Tiwari S, Shankar J. Integrated proteome and HPLC analysis revealed quercetin-mediated inhibition of aflatoxin B1 biosynthesis in Aspergillus flavus. 3 Biotech  2018; 8(1): 47.
[127] 
Negri M, Salci TP, Shinobu-Mesquita CS, Capoci IRG, Svidzinski TIE, Kioshima ES. Early state research on antifungal natural products. Molecules  2014; 19(3): 2925-56.
[http://dx.doi.org/10.3390/molecules19032925] [PMID: 24609016] 
[128] 
Li W-R, Shi Q-S, Dai H-Q, et al. Antifungal activity, kinetics and molecular mechanism of action of garlic oil against Candida albicans. Sci Rep  2016; 6: 22805.
[http://dx.doi.org/10.1038/srep22805] [PMID: 26948845] 
[129] 
Fiorini A, Rosado FR, Bettega EM da S, et al. Candida albicans protein profile changes in response to the butanolic extract of Sapindus saponariaL. Rev Inst Med Trop São Paulo  2016; 58: 25.
[http://dx.doi.org/10.1590/s1678-9946201658025] [PMID: 27074319] 
[130] 
Komatsu T, Salih E, Helmerhorst EJ, Offner GD, Oppenheim FG. Influence of histatin 5 on Candida albicans mitochondrial protein expression assessed by quantitative mass spectrometry. J Proteome Res  2011; 10(2): 646-55.
[http://dx.doi.org/10.1021/pr100861k] [PMID: 21080726] 
[131] 
Prado RS, Bailão AM, Silva LC, et al. Proteomic profile response of Paracoccidioides lutzii to the antifungal argentilactone. Front Microbiol  2015; 6: 616.
[http://dx.doi.org/10.3389/fmicb.2015.00616] [PMID: 26150808] 
[132] 
Silva LDC, Tauhata SBF, Baeza LC, et al. Argentilactone molecular targets in Paracoccidioides brasiliensis identified by chemoproteomics. Antimicrob Agents Chemother  2018; 62(11): e00737-18.
[http://dx.doi.org/10.1128/AAC.00737-18] [PMID: 30150478] 
[133] 
Borba JVVB, Tauhata SBF, Oliveira CMA, et al. Chemoproteomic identification of molecular targets of antifungal prototypes, thiosemicarbazide and a camphene derivative of thiosemicarbazide, in Paracoccidioides brasiliensis. PLoS One  2018; 13(8) e0201948
[http://dx.doi.org/10.1371/journal.pone.0201948] [PMID: 30148835] 
[134] 
Wächtler B, Wilson D, Haedicke K, Dalle F, Hube B. From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS One  2011; 6(2) e17046
[http://dx.doi.org/10.1371/journal.pone.0017046] [PMID: 21407800] 
[135] 
Fox EP, Nobile CJ. A sticky situation: untangling the transcriptional network controlling biofilm development in Candida albicans. Transcription  2012; 3(6): 315-22.
[http://dx.doi.org/10.4161/trns.22281] [PMID: 23117819] 
[136] 
Nobile CJ, Fox EP, Nett JE, et al. A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell  2012; 148(1-2): 126-38.
[http://dx.doi.org/10.1016/j.cell.2011.10.048] [PMID: 22265407] 
[137] 
Ghannoum M, Roilides E, Katragkou A, Petraitis V, Walsh TJ. The role of echinocandins in Candida biofilm-related vascular catheter infections: in vitro and in vivo model systems. Clin Infect Dis  2015; 61(Suppl. 6): S618-21.
[http://dx.doi.org/10.1093/cid/civ815] [PMID: 26567279] 
[138] 
Kean R, Delaney C, Sherry L, et al. Transcriptome assembly and profiling of candida auris reveals novel insights into biofilm-mediated resistance. MSphere  2018; 3(4): e00334-18.
[http://dx.doi.org/10.1128/mSphere.00334-18] [PMID: 29997121] 
[139] 
Cavalheiro M, Costa C, Silva-Dias A, et al. A transcriptomics approach to unveiling the mechanisms of in vitro evolution towards fluconazole resistance of a Candida glabrata clinical isolate. Antimicrob Agents Chemother  2018; 63(1): e00995-18.
[http://dx.doi.org/10.1128/AAC.00995-18] [PMID: 30348666] 
[140] 
Yang Q, Gao L, Tao M, Chen Z, Yang X, Cao Y. Transcriptomics analysis of Candida albicans treated with huanglian jiedu decoction using RNA-seq. Evidence-Based Complementary and Alternative Medicine (2016).Available from:. https://www.hindawi.com/ journals/ ecam/2016/3198249/
[141] 
Romo JA, Zhang H, Cai H, et al. Global transcriptomic analysis of the candida albicans response to treatment with a novel inhibitor of filamentation. MSphere  2019; 4(5): e00620-19.
[http://dx.doi.org/10.1128/mSphere.00620-19] [PMID: 31511371] 
[142] 
Russo P, Fares C, Longo A, Spano G, Capozzi V. Lactobacillus plantarum with broad antifungal activity as a protective starter culture for bread production. Foods  2017; 6(12) E110
[http://dx.doi.org/10.3390/foods6120110] [PMID: 29232917] 
[143] 
Crowley S, Mahony J, Morrissey JP, van Sinderen D. Transcriptomic and morphological profiling of Aspergillus fumigatus Af293 in response to antifungal activity produced by Lactobacillus plantarum 16. Microbiology  2013; 159(Pt 10): 2014-24.
[http://dx.doi.org/10.1099/mic.0.068742-0] [PMID: 23876797] 
[144] 
Perkhofer S, Kainzner B, Kehrel BE, Dierich MP, Nussbaumer W, Lass-Flörl C. Potential antifungal effects of human platelets against zygomycetes in vitro. J Infect Dis  2009; 200(7): 1176-9.
[http://dx.doi.org/10.1086/605607] [PMID: 19698079] 
[145] 
Perkhofer S, Zenzmaier C, Frealle E, et al. Differential gene expression in Aspergillus fumigatus induced by human platelets in vitro. Int J Med Microbiol  2015; 305(3): 327-38.
[http://dx.doi.org/10.1016/j.ijmm.2015.01.002] [PMID: 25661519] 
[146] 
Woyke T, Berens ME, Hoelzinger DB, Pettit GR, Winkelmann G, Pettit RK. Differential gene expression in auristatin PHE-treated Cryptococcus neoformans. Antimicrob Agents Chemother  2004; 48(2): 561-7.
[http://dx.doi.org/10.1128/AAC.48.2.561-567.2004] [PMID: 14742210] 
[147] 
Zhang L, Zhang Y, Zhou Y, An S, Zhou Y, Cheng J. Response of gene expression in Saccharomyces cerevisiae to amphotericin B and nystatin measured by microarrays. J Antimicrob Chemother  2002; 49(6): 905-15.
[http://dx.doi.org/10.1093/jac/dkf001] [PMID: 12039882] 
[148] 
do Carmo Silva L, Tamayo Ossa DP, Castro SV, et al. Transcriptome profile of the response of paracoccidioides spp. to a camphene thiosemicarbazide derivative. PLoS One  2015; 10(6) e0130703
[http://dx.doi.org/10.1371/journal.pone.0130703] [PMID: 26114868] 
[149] 
Nosengo N. Can you teach old drugs new tricks? Nature  2016; 534(7607): 314-6.
[http://dx.doi.org/10.1038/534314a] [PMID: 27306171] 
[150] 
Kantarjian HM, Prat F, Steensma DP, et al. Cancer research in the United States: A critical review of current status and proposal for alternative models. Cancer  2018; 124(14): 2881-9.
[http://dx.doi.org/10.1002/cncr.31522] [PMID: 29757456] 
[151] 
DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ  2016; 47: 20-33.
[http://dx.doi.org/10.1016/j.jhealeco.2016.01.012] [PMID: 26928437] 
[152] 
Moore TJ, Zhang H, Anderson G, Alexander GC. Estimated costs of pivotal trials for novel therapeutic agents approved by the US food and drug administration, 2015-2016. JAMA Intern Med  2018; 178(11): 1451-7.
[http://dx.doi.org/10.1001/jamainternmed.2018.3931] [PMID: 30264133] 
[153] 
Ekins S, Puhl AC, Zorn KM, et al. Exploiting machine learning for end-to-end drug discovery and development. Nat Mater  2019; 18(5): 435-41.
[http://dx.doi.org/10.1038/s41563-019-0338-z] [PMID: 31000803] 
[154] 
Zhavoronkov A, Ivanenkov YA, Aliper A, et al. Deep learning enables rapid identification of potent DDR1 kinase inhibitors. Nat Biotechnol  2019; 37(9): 1038-40.
[http://dx.doi.org/10.1038/s41587-019-0224-x] [PMID: 31477924] 
[155] 
Lavecchia A. Machine-learning approaches in drug discovery: methods and applications. Drug Discov Today  2015; 20(3): 318-31.
[http://dx.doi.org/10.1016/j.drudis.2014.10.012] [PMID: 25448759] 
[156] 
Gaulton A, Bellis LJ, Bento AP, et al. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res  2012; 40(Database issue): D1100-7.
[http://dx.doi.org/10.1093/nar/gkr777] [PMID: 21948594] 
[157] 
Wang Y, Xiao J, Suzek TO, et al. PubChem’s BioAssay Database. Nucleic Acids Res  2012; 40(Database issue): D400-12.
[http://dx.doi.org/10.1093/nar/gkr1132] [PMID: 22140110] 
[158] 
Wang Y, Bolton E, Dracheva S, et al. An overview of the PubChem BioAssay resource. Nucleic Acids Res  2010; 38(Database issue): D255-66.
[http://dx.doi.org/10.1093/nar/gkp965] [PMID: 19933261] 
[159] 
Fourches D, Muratov E, Tropsha A, Fourchers D, Muratov E, Tropsha A. Trust, but verify: on the importance of chemical structure curation in cheminformatics and QSAR modeling research. J Chem Inf Model  2010; 50(7): 1189-204.
[http://dx.doi.org/10.1021/ci100176x] [PMID: 20572635] 
[160] 
Fourches D, Muratov E, Tropsha A. Curation of chemogenomics data. Nat Chem Biol  2015; 11(8): 535-5.
[http://dx.doi.org/10.1038/nchembio.1881] [PMID: 26196763] 
[161] 
Fourches D, Muratov E, Tropsha A. Trust, but Verify II: A practical guide to chemogenomics data curation. J Chem Inf Model  2016; 56(7): 1243-52.
[http://dx.doi.org/10.1021/acs.jcim.6b00129] [PMID: 27280890] 
[162] 
Carlson BM. Human embryology and developmental biology.  3rd ed. St. Louis: Mosby 2004.
[163] 
Svetnik V, Liaw A, Tong C, Culberson JC, Sheridan RP, Feuston BP. Random forest: a classification and regression tool for compound classification and QSAR modeling. J Chem Inf Comput Sci  2003; 43(6): 1947-58.
[http://dx.doi.org/10.1021/ci034160g] [PMID: 14632445] 
[164] 
Breiman LEO. Random Forests. Mach Learn  2001; 45: 5-32.
[http://dx.doi.org/10.1023/A:1010933404324] 
[165] 
Cherkasov A, Muratov EN, Fourches D, et al. QSAR modeling: where have you been? Where are you going to? J Med Chem  2014; 57(12): 4977-5010.
[http://dx.doi.org/10.1021/jm4004285] [PMID: 24351051] 
[166] 
Tanrikulu Y, Krüger B, Proschak E. The holistic integration of virtual screening in drug discovery. Drug Discov Today  2013; 18(7-8): 358-64.
[http://dx.doi.org/10.1016/j.drudis.2013.01.007] [PMID: 23340112] 
[167] 
Kar S, Roy K. How far can virtual screening take us in drug discovery? Expert Opin Drug Discov  2013; 8(3): 245-61.
[http://dx.doi.org/10.1517/17460441.2013.761204] [PMID: 23330660] 
[168] 
OECD principles for the validation, for regulatory purposes, of (Quantitative) structure-activity relationship models. organisation for economic cooperation and development  1-2.(2004); Available from:. http://www.oecd.org/ chemicalsafety/risk-assessment/37849783.pdf
[169] 
Gadaleta D, Mangiatordi GF, Catto M, Carotti A, Nicolotti O. Applicability domain for QSAR models. Int J Quant Struc Prop Rel  2016; 1(1): 45-63.
[http://dx.doi.org/10.4018/IJQSPR.2016010102] 
[170] 
Netzeva TI, Worth A, Aldenberg T, et al. Current status of methods for defining the applicability domain of (quantitative) structureactivity relationships. The report and recommendations of ECVAM Workshop 52  Alternatives to laboratory animals : ATLA.. 33(2): 155-73.
[171] 
Mathea M, Klingspohn W, Baumann K. Chemoinformatic classification methods and their applicability domain. Mol Inform  2016; 35(5): 160-80.
[http://dx.doi.org/10.1002/minf.201501019] [PMID: 27492083] 
[172] 
Ekins S. The next era: deep learning in pharmaceutical research. Pharm Res  2016; 33(11): 2594-603.
[http://dx.doi.org/10.1007/s11095-016-2029-7] [PMID: 27599991] 
[173] 
Chen H, Kogej T, Engkvist O. Cheminformatics in drug discovery, an industrial perspective. Mol Inform  2018; 37(9-10) e1800041
[http://dx.doi.org/10.1002/minf.201800041] [PMID: 29774657] 
[174] 
Chen H, Engkvist O, Wang Y, Olivecrona M, Blaschke T. The rise of deep learning in drug discovery. Drug Discov Today  2018; 23(6): 1241-50.
[http://dx.doi.org/10.1016/j.drudis.2018.01.039] [PMID: 29366762] 
[175] 
Shen C, Wang X, Zheng Z, et al. Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma. Int J Nanomedicine  2018; 14: 101-17.
[http://dx.doi.org/10.2147/IJN.S173954] [PMID: 30587988] 
[176] 
Lo Y-C, Rensi SE, Torng W, Altman RB. Machine learning in chemoinformatics and drug discovery. Drug Discov Today  2018; 23(8): 1538-46.
[http://dx.doi.org/10.1016/j.drudis.2018.05.010] [PMID: 29750902] 
[177] 
Srivastava N, Hinton G, Krizhevsky A, Sutskever I, Salakhutdinov R. Dropout: a simple way to prevent neural networks from overfitting. J Mach Learn Res  2014; 15: 1929-58.
[178] 
Meissner M, Schmuker M, Schneider G. Optimized Particle Swarm Optimization (OPSO) and its application to artificial neural network training. BMC Bioinformatics  2006; 7: 125.
[http://dx.doi.org/10.1186/1471-2105-7-125] [PMID: 16529661] 
[179] 
Kingma DP, Ba J. Adam: A Method for Stochastic Optimization 2014.
[180] 
Yang X, Wang Y, Byrne R, Schneider G, Yang S. Concepts of artificial intelligence for computer-assisted drug discovery. Chem Rev  2019; 119(18): 10520-94.
[http://dx.doi.org/10.1021/acs.chemrev.8b00728] [PMID: 31294972] 
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DOI https://dx.doi.org/10.2174/1381612826666200317125956	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286
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