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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

The Custom R Group Enumeration with Various R Group Libraries at Designated Sites on Amphotericin B

Author(s): Ajay Mahor, Devesh M. Sawant and Amit K. Goyal*

Volume 19, Issue 5, 2023

Published on: 08 February, 2023

Page: [382 - 390] Pages: 9

DOI: 10.2174/1573409919666230123144712

Price: $65

Abstract

Background: Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups.

Methods: Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties.

Results: We identified fourteen hits with improved predicted aqueous solubility and cell permeability.

Conclusion: Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.

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[1]
Sampaio, J.P.; Gadanho, M.; Bauer, R.; Weiß, M. Taxonomic studies in the Microbotryomycetidae: Leucosporidium golubevii sp. nov., Leucosporidiella gen. nov. and the new orders Leucosporidiales and Sporidiobolales. Mycol. Prog., 2003, 2(1), 53-68.
[http://dx.doi.org/10.1007/s11557-006-0044-5]
[2]
Sant, D.G.; Tupe, S.G.; Ramana, C.V.; Deshpande, M.V. Fungal cell membrane-promising drug target for antifungal therapy. J. Appl. Microbiol., 2016, 121(6), 1498-1510.
[http://dx.doi.org/10.1111/jam.13301] [PMID: 27667746]
[3]
Solovieva, S.E.; Olsufyeva, E.N.; Preobrazhenskaya, M.N. Chemical modification of antifungal polyene macrolide antibiotics. Russ. Chem. Rev., 2011, 80(2), 103-126.
[http://dx.doi.org/10.1070/RC2011v080n02ABEH004145]
[4]
Hamill, R.J.; Amphotericin, B. Amphotericin B formulations: A comparative review of efficacy and toxicity. Drugs, 2013, 73(9), 919-934.
[http://dx.doi.org/10.1007/s40265-013-0069-4] [PMID: 23729001]
[5]
Laniado-Laborín, R.; Cabrales-Vargas, M.N.; Amphotericin, B.; Amphotericin, B. Side effects and toxicity. Rev. Iberoam. Micol., 2009, 26(4), 223-227.
[http://dx.doi.org/10.1016/j.riam.2009.06.003] [PMID: 19836985]
[6]
Dutta, A.; Palazzi, D.L. Risk factors of amphotericin B toxicty in the nonneonatal pediatric population. Pediatr. Infect. Dis. J., 2012, 31(9), 910-914.
[http://dx.doi.org/10.1097/INF.0b013e31825d649a] [PMID: 22581225]
[7]
Czerwiński, A.; Grzybowska, J.; Borowski, E. N-dimethylaminoacyl derivatives of polyene macrolide antibiotics. J. Antibiot., 1986, 39(7), 1025-1027.
[http://dx.doi.org/10.7164/antibiotics.39.1025] [PMID: 3759647]
[8]
Omelchuk, O.A.; Tevyashova, A.N.; Shchekotikhin, A.E. Recent advances in antifungal drug discovery based on polyene macrolide antibiotics. Russ. Chem. Rev., 2018, 87(12), 1206-1225.
[http://dx.doi.org/10.1070/RCR4841]
[9]
Wang, J.; Ma, Y.; Hou, S.; Miao, Z.; Ma, Q. Interaction of amphotericin B and saturated or unsaturated phospholipid monolayers containing cholesterol or ergosterol at the air-water interface. Biophys. Chem., 2020, 258106317
[http://dx.doi.org/10.1016/j.bpc.2019.106317] [PMID: 31918025]
[10]
Ferdosian, M.; Sardari, S. A novel mechanistic approach to identify new antifungal lead compounds based on amphotericin B molecular architecture. Trop. J. Pharm. Res., 2013, 12(2), 181-188.
[http://dx.doi.org/10.4314/tjpr.v12i2.8]
[11]
Halperin, A.; Shadkchan, Y.; Pisarevsky, E.; Szpilman, A.M.; Sandovsky, H.; Osherov, N.; Benhar, I. Novel water-soluble amphotericin b-peg conjugates with low toxicity and potent in vivo efficacy. J. Med. Chem., 2016, 59(3), 1197-1206.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01862] [PMID: 26816333]
[12]
Markovic, M.; Zur, M.; Ragatsky, I.; Cvijić, S.; Dahan, A. BCS class IV oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide. Pharmaceutics, 2020, 12(12), 1175.
[http://dx.doi.org/10.3390/pharmaceutics12121175] [PMID: 33276565]
[13]
Dahan, A.; Miller, J.M.; Amidon, G.L. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. AAPS J., 2009, 11(4), 740-746.
[http://dx.doi.org/10.1208/s12248-009-9144-x] [PMID: 19876745]
[14]
Nicolaou, K.C.; Chakraborty, T.K.; Daines, R.A.; Simpkins, N.S. Retrosynthetic and synthetic chemistry on amphotericin B. Synthesis of C(1-C(20) and C(21)-C(38) fragments and construction of the 38-membered macrocycle. J. Chem. Soc. Chem. Commun., 1986, (5), 413-416.
[http://dx.doi.org/10.1039/C39860000413]
[15]
Liu, M.; Chen, M.; Yang, Z. Design of amphotericin B oral formulation for antifungal therapy., 2017, 24, 1-9.
[http://dx.doi.org/10.1080/10717544.2016.1225852]
[16]
CombiGlide. Version 3.7; Schrodinger, LLC: New York, NY, 2015.
[17]
Sud, M.; Fahy, E.; Subramaniam, S. Template-based combinatorial enumeration of virtual compound libraries for lipids. J. Cheminform., 2012, 4(1), 23.
[http://dx.doi.org/10.1186/1758-2946-4-23] [PMID: 23006594]
[18]
Mustard, T; Hughes, T; Bochevarov, A; Jacobson, L; Kwak, H; Morisato, T; Gavartin, J; Pandiyan, S; Halls, M Automated high throughput in silico reaction screening for design and discovery of enhanced reactivity and tailored chemo-, regio-, and stereoselectivity. Amer Chemical Soc: Washington DC 20036 USA.
[19]
Konze, K.D.; Bos, P.H.; Dahlgren, M.K.; Leswing, K.; Tubert-Brohman, I.; Bortolato, A.; Robbason, B.; Abel, R.; Bhat, S. Reaction-based enumeration, active learning, and free energy calculations to rapidly explore synthetically tractable chemical space and optimize potency of cyclin-dependent kinase 2 inhibitors. J. Chem. Inf. Model., 2019, 59(9), 3782-3793.
[http://dx.doi.org/10.1021/acs.jcim.9b00367] [PMID: 31404495]
[20]
Saldívar-González, F.I.; Huerta-García, C.S.; Medina-Franco, J.L. Chemoinformatics-based enumeration of chemical libraries: A tutorial. J. Cheminform., 2020, 12(1), 64.
[http://dx.doi.org/10.1186/s13321-020-00466-z] [PMID: 33372622]
[21]
Mohlala, L.M.; Jen, T.C.; Olubambi, P.A. Thermal stability and reactivity of titanium halide precursors for the atomic layer deposition of TiO2 on a Pt (111) surface. Proceedings of the Procedia CIRP, 2020, 93, 9-13.
[22]
Library Design. Enumeration Tools., 2017.
[23]
Adediran, S.A.; Day, T.P.; Sil, D.; Kimbrell, M.R.; Warshakoon, H.J.; Malladi, S.S.; David, S.A. Synthesis of a highly water-soluble derivative of amphotericin B with attenuated proinflammatory activity. Mol. Pharm., 2009, 6(5), 1582-1590.
[http://dx.doi.org/10.1021/mp9001602] [PMID: 19663403]
[24]
Update, S. suite 2012. QikProp descriptors and properties PISA. 2012.
[25]
Shaikh, F.; Siu, S.W.I. Identification of novel natural compound inhibitors for human complement component 5a receptor by homology modeling and virtual screening. Med. Chem. Res., 2016, 25(8), 1564-1573.
[http://dx.doi.org/10.1007/s00044-016-1591-1] [PMID: 27499603]
[26]
Adnan, M.; Nazim Uddin Chy, M.; Mostafa Kamal, A.T.M.; Azad, M.; Paul, A.; Uddin, S.; Barlow, J.; Faruque, M.; Park, C.; Cho, D. Investigation of the biological activities and characterization of bioactive constituents of Ophiorrhiza rugosa var. prostrata (D.Don) and mondal leaves through in vivo, in vitro, and in silico approaches. Molecules, 2019, 24(7), 1367.
[http://dx.doi.org/10.3390/molecules24071367] [PMID: 30965575]
[27]
Filimonov, D.A.; Rudik, A.V.; Dmitriev, A.V.; Poroikov, V.V. Computer-aided estimation of biological activity profiles of drug-like compounds taking into account their metabolism in human body. Int. J. Mol. Sci., 2020, 21(20), 7492.
[http://dx.doi.org/10.3390/ijms21207492] [PMID: 33050610]
[28]
Ioakimidis, L.; Thoukydidis, L.; Mirza, A.; Naeem, S.; Reynisson, J. Benchmarking the reliability of QikProp. Correlation between experimental and predicted values. QSAR Comb. Sci., 2008, 27(4), 445-456.
[http://dx.doi.org/10.1002/qsar.200730051]
[29]
Işık, M.; Levorse, D.; Mobley, D.L.; Rhodes, T.; Chodera, J.D. Octanol-water partition coefficient measurements for the SAMPL6 blind prediction challenge. J. Comput. Aided Mol. Des., 2020, 34(4), 405-420.
[http://dx.doi.org/10.1007/s10822-019-00271-3] [PMID: 31858363]
[30]
Anupriya, G.; Roopa, K.; Basappa, S.; Chong, Y.S.; Annamalai, L. Homology modeling and in silico screening of inhibitors for the substrate binding domain of human Siah2: Implications for hypoxia-induced cancers. J. Mol. Model., 2011, 17(12), 3325-3332.
[http://dx.doi.org/10.1007/s00894-011-1025-4] [PMID: 21409570]
[31]
Coltescu, A.R.; Butnariu, M.; Sarac, I. The importance of solubility for new drug molecules. Biomed. Pharmacol. J., 2020, 13(2), 577-583.
[http://dx.doi.org/10.13005/bpj/1920]
[32]
Kothapalli, R.; Khan, A.M.; Gopalsamy, A.; Chong, Y.S. Cheminformatics-based drug design approach for identification of inhibitors targeting the characteristic residues of MMP-13 hemopexin cheminformatics-based drug design approach for identification of inhibitors targeting the characteristic residues of MMP. PLoS One, 2010, 5(8)e12494
[http://dx.doi.org/10.1371/journal.pone.0012494] [PMID: 20824169]
[33]
Hubatsch, I.; Ragnarsson, E.G.E.; Artursson, P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc., 2007, 2, 2111-2119.
[34]
Ntie-Kang, F. An in silico evaluation of the ADMET profile of the StreptomeDB database. Springerplus, 2013, 2(1), 353.
[http://dx.doi.org/10.1186/2193-1801-2-353] [PMID: 23961417]
[35]
Ricci-López, J.; Vidal-Limon, A.; Zunñiga, M.; Jimènez, V.A.; Alderete, J.B.; Brizuela, C.A.; Aguila, S. Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein. PLoS One, 2019, 14(3)e0213028
[http://dx.doi.org/10.1371/journal.pone.0213028] [PMID: 30875378]
[36]
Benet, L.Z.; Hosey, C.M.; Ursu, O.; Oprea, T.I. BDDCS, the rule of 5 and drugability. Adv. Drug Deliv. Rev., 2016, 101, 89-98.
[http://dx.doi.org/10.1016/j.addr.2016.05.007] [PMID: 27182629]
[37]
Baginski, M.; Czub, J. Amphotericin B and its new derivatives: mode of action. Curr. Drug Metab., 2009, 10(5), 459-469.
[http://dx.doi.org/10.2174/138920009788898019] [PMID: 19689243]
[38]
Paquet, V.; Carreira, E.M. Significant improvement of antifungal activity of polyene macrolides by bisalkylation of the mycosamine. Org. Lett., 2006, 8(9), 1807-1809.
[http://dx.doi.org/10.1021/ol060353o] [PMID: 16623556]
[39]
Tevyashova, A.N.; Olsufyeva, E.N.; Solovieva, S.E.; Printsevskaya, S.S.; Reznikova, M.I.; Trenin, A.S.; Galatenko, O.A.; Treshalin, I.D.; Pereverzeva, E.R.; Mirchink, E.P.; Isakova, E.B.; Zotchev, S.B.; Preobrazhenskaya, M.N. Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group. Antimicrob. Agents Chemother., 2013, 57(8), 3815-3822.
[http://dx.doi.org/10.1128/AAC.00270-13] [PMID: 23716057]
[40]
Borowski, E.; Salewska, N.; Boros-Majewska, J.; Serocki, M.; Chabowska, I.; Milewska, M.J.; Ziętkowski, D.; Milewski, S. The substantial improvement of amphotericin b selective toxicity upon modification of mycosamine with bulky substituents. Med. Chem., 2020, 16(1), 128-139.
[http://dx.doi.org/10.2174/1573406415666181203114629] [PMID: 30501601]
[41]
Schaffner Carl, P.; Witold, M. Derivatives of polyene macrolide antibiotics. US3945993A.
[42]
Chang, Conway C.; Dang, Binh, T.; Baldwin, Christopher, J.; Loury, David, J.; Simon, Reyna, J.; WEBB, Robert, R. Watersoluble amide derivatives of polyene macrolides and preparation and uses thereof. WO/2001/091758, 2015.
[43]
Tevyashova, A.N.; Korolev, A.M.; Trenin, A.S.; Dezhenkova, L.G.; Shtil, A.A.; Polshakov, V.I.; Savelyev, O.Y.; Olsufyeva, E.N. New conjugates of polyene macrolide amphotericin B with benzoxaboroles: synthesis and properties. J. Antibiot., 2016, 69(7), 549-560.
[http://dx.doi.org/10.1038/ja.2016.34] [PMID: 27005557]
[44]
Borowski, E.; Salewska, N.; Boros-Majewska, J.; Milewska, M.; Wysocka, M.; Milewski, S. Łącka, I.; Sabisz, M. N-substituted second generation derivaties of antifungal antibiotic amphotericin b and methods of thier preparation and application. WO 2013/186384 Al, 2014.
[45]
Belakhov, V.V.; Kolodyaznaya, V.A.; Garabadzhiu, A.V. Chemical modification of heptaene macrolide antibiotic Amphotericin B under conditions of the Atherton-Todd reaction. Russ. J. Gen. Chem., 2014, 84(10), 1953-1961.
[http://dx.doi.org/10.1134/S107036321410017X]
[46]
Zhang, J.; Ma, J.; Dong, Y.; Zhao, W.; Feng, J. Synthesis and characterization of NH2-(AEEA)n-amphotericin B derivatives. J. Antibiot. (Tokyo), 2019, 72(4), 210-217.
[http://dx.doi.org/10.1038/s41429-018-0138-8] [PMID: 30635615]
[47]
Ishikawa, M.; Hashimoto, Y. Improving the Water-Solubility of Compounds By Molecular Modification to Disrupt Crystal Packing; Elsevier Ltd: Amsterdam, 2015, Vol. 5, pp. 745-765.
[http://dx.doi.org/10.1016/B978-0-12-417205-0.00031-6]
[48]
Ashp. Functional Group Characteristics and Roles. In. Marc W.H.; Robin, M.Z.; (Eds.) Basic Concepts in Medicinal Chemistry, London, American Society of Health-System Pharmacists, 2017, pp. 36.
[49]
Mahor, A.; Sawant, D.M.; Goyal, A.K. Chemical and physical approaches for improved biopharmaceutical activity of amphotericin B: Current and future prospective. Curr. Top. Med. Chem., 2022, 22(19), 1571-1592.

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