Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Pharmacophore Based Design of Probable FGFR-1 Inhibitors from the 3D Crystal Structure of Infigratinib - A Drug Used in the Treatment of Cholangiocarcinomas

Author(s): Koushik Sarker , Avijit Ghosh , Abhijit Saha, Suvasish Mishra and Subrata Sen*

Volume 19, Issue 4, 2022

Published on: 07 October, 2021

Page: [314 - 322] Pages: 9

DOI: 10.2174/1570180818666211007113720

Price: $65

Abstract

Background: Pemigatinib (INCB054828) and Infigratinib (BGJ398) are the few selective drugs that are approved by the FDA to treat cholangiocarcinoma, a rare form of bile duct cancer. Infigratinib is a pan FGFR inhibitor and has been found promising in Phase-3, first-line PROOF clinical trial. So, screening drug-like compounds having similar pharmacophoric features like infigratinib is the inspiration of the present work.

Objective: The objective was to identify drug-like compounds with similar pharmacophoric features as in infigratinib. The compounds screened through the 3D query pharmacophore of infigratinib were also predicted for ADMET properties so that the compounds may have good bioavailability.

Methods: A pharmacophore was generated from the crystal structure of infigratinib with several pharmacophoric features such as hydrogen bond donor, hydrophobic, positive ionizable, and ring aromatic. MayBridge database containing 65,263 compounds was used for virtual screening (VS) using LibDock. The initial Hit compounds were subjected to ADMET predictions. Finally, two Hit compounds were selected and docked with the FGFR-1 receptor to predict the interaction of the ligand atoms with the amino acid residues of the receptor's active site.

Results: The fit score for infigratinib, N-(4-fluorophenyl)-2-(5-((2-(4-methoxy-2,5-dimethylphenyl)-2- oxoethyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)acetamide (Hit-1) and 4-(4-((2-(5,6-dimethyl-1H-benzo[d] imidazol-2-yl)ethyl)carbamoyl)pyridin-2-yl)-1-methylpiperazin-1-ium (Hit-4) is 4.58901, 4.36649, and 3.71732, respectively. The LibDock score of infigratinib, Hit-1, and Hit-4 is 122.474, 123.289, and 123.353, respectively. The binding affinity score (-PLP1) of infigratinib, Hit-1, and Hit-4 is -143.19, - 102.72, and -91.71.

Conclusion: The present study concluded that the two compounds designated as Hit-1 and Hit-4 have been identified as binders of FGFR-1, and Hit-4 occupies the whole pharmacophoric space of infigratinib, and both the compounds LibDock scores are better than the infigratinib. The two compounds Hit-1 and Hit-4 may be synthesized and studied for their enzyme inhibition assay on FGFR-1 and biologically evaluated on different cell lines for Cholangiocarcinoma.

Keywords: Cholangiocarcinoma, infigratinib, pharmacophore, virtual screening, docking, ADMET.

« Previous Next »
Graphical Abstract

[1]
Vincent, T.D.; Theodore, S.L.; Steven, A.R. Cancer of the Biliary Tree.In: Wolter Kluwer, 11th edition; , 2019; p. 865.
[2]
Gomaa, A.I.; Khan, S.A.; Toledano, M.B.; Waked, I.; Taylor-Robinson, S.D. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J. Gastroenterol., 2008, 14(27), 4300-4308.
[http://dx.doi.org/10.3748/wjg.14.4300] [PMID: 18666317]
[3]
Ishak, K.G.; Anthony, P.P.; Sobin, L.H. Histological classification of tumours of the liver.In: World Health Organization. International Histological Classification of Tumours; Springer: Berlin, Heidelberg 1994, 5-7.
[http://dx.doi.org/10.1007/978-3-642-85156-8_2]
[4]
Tyson, G.L.; El-Serag, H.B. Risk factors for cholangiocarcinoma. Hepatology, 2011, 54(1), 173-184.
[http://dx.doi.org/10.1002/hep.24351] [PMID: 21488076]
[5]
Grainge, M.J.; West, J.; Solaymani-Dodaran, M.; Aithal, G.P.; Card, T.R. The antecedents of biliary cancer: a primary care case-control study in the United Kingdom. Br. J. Cancer, 2009, 100(1), 178-180.
[http://dx.doi.org/10.1038/sj.bjc.6604765] [PMID: 19018260]
[6]
Taylor-Robinson, S.D.; Toledano, M.B.; Arora, S.; Keegan, T.J.; Hargreaves, S.; Beck, A.; Khan, S.A.; Elliott, P.; Thomas, H.C. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut, 2001, 48(6), 816-820.
[http://dx.doi.org/10.1136/gut.48.6.816] [PMID: 11358902]
[7]
Sia, D.; Tovar, V.; Moeini, A.; Llovet, J.M. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene, 2013, 32(41), 4861-4870.
[http://dx.doi.org/10.1038/onc.2012.617] [PMID: 23318457]
[8]
Aishima, S.I.; Taguchi, K.I.; Sugimachi, K.; Shimada, M.; Sugimachi, K.; Tsuneyoshi, M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology, 2002, 40(3), 269-278.
[http://dx.doi.org/10.1046/j.1365-2559.2002.00353.x] [PMID: 11895493]
[9]
Jain, A.; Borad, M.J.; Kelley, R.K.; Wang, Y.; Abdel-Wahab, R.; Meric-Bernstam, F. Cholangiocarcinoma with FGFR genetic aberrations: A unique clinical phenotype. JCO Precis. Oncol., 2018, 2, 1-12.
[http://dx.doi.org/10.1200/PO.17.00080]
[10]
Knowles, M.A.; Hurst, C.D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer, 2015, 15(1), 25-41.
[http://dx.doi.org/10.1038/nrc3817] [PMID: 25533674]
[11]
Patel, T. Cholangiocarcinoma--controversies and challenges. Nat. Rev. Gastroenterol. Hepatol., 2011, 8(4), 189-200.
[http://dx.doi.org/10.1038/nrgastro.2011.20] [PMID: 21460876]
[12]
Ramírez-Merino, N.; Aix, S.P.; Cortés-Funes, H. Chemotherapy for cholangiocarcinoma: An update. World J. Gastrointest. Oncol., 2013, 5(7), 171-176.
[http://dx.doi.org/10.4251/wjgo.v5.i7.171] [PMID: 23919111]
[13]
Park, J.O.; Oh, D.Y.; Hsu, C.; Chen, J.S.; Chen, L.T.; Orlando, M.; Kim, J.S.; Lim, H.Y. Gemcitabine plus cisplatin for advanced biliary tract cancer: A systematic review. Cancer Res. Treat., 2015, 47(3), 343-361.
[http://dx.doi.org/10.4143/crt.2014.308] [PMID: 25989801]
[14]
Vivian, S.; Nathan, B.; Anna, S.; Lisa, K.; Paul, M.; Katherine, N.; Kenneth, R.; Sandaruwan, G.; Raymond, G.; Steven, M.C.; Jean-Emmanuel, S.; Mary, S.; Courtney, D.; Marina, K. Abstract 6417: LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML). Cancer Res., 2020, 80, 6417.
[http://dx.doi.org/10.1158/1538-7445.AM2020-6417]
[15]
Cohen, A.L.; Holmen, S.L.; Colman, H. IDH1 and IDH2 mutations in gliomas. Curr. Neurol. Neurosci. Rep., 2013, 13(5), 345.
[http://dx.doi.org/10.1007/s11910-013-0345-4] [PMID: 23532369]
[16]
Yen, K.E.; Schenkein, D.P. Cancer-associated isocitrate dehydrogenase mutations. Oncologist, 2012, 17(1), 5-8.
[http://dx.doi.org/10.1634/theoncologist.2011-0429] [PMID: 22234630]
[17]
Borger, D.R.; Tanabe, K.K.; Fan, K.C.; Lopez, H.U.; Fantin, V.R.; Straley, K.S.; Schenkein, D.P.; Hezel, A.F.; Ancukiewicz, M.; Liebman, H.M.; Kwak, E.L.; Clark, J.W.; Ryan, D.P.; Deshpande, V.; Dias-Santagata, D.; Ellisen, L.W.; Zhu, A.X.; Iafrate, A.J. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist, 2012, 17(1), 72-79.
[http://dx.doi.org/10.1634/theoncologist.2011-0386] [PMID: 22180306]
[18]
Liu, P.C.C.; Koblish, H.; Wu, L.; Bowman, K.; Diamond, S.; DiMatteo, D.; Zhang, Y.; Hansbury, M.; Rupar, M.; Wen, X.; Collier, P.; Feldman, P.; Klabe, R.; Burke, K.A.; Soloviev, M.; Gardiner, C. He., X.; Volgina, A.; Covington, M.; Ruggeri, B.; Wynn, R.; Burn, T.C.; Scherle, P.; Yeleswaram, S.; Yao, W.; Huber, R.; Hollis, G. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. PLoS One, 2020, 15(4), e0231877.
[http://dx.doi.org/10.1371/journal.pone.0231877] [PMID: 32315352]
[19]
Katoh, M. FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis. (Review) Int. J. Mol. Med., 2016, 38(1), 3-15.
[http://dx.doi.org/10.3892/ijmm.2016.2620] [PMID: 27245147]
[20]
Phase IIa study of the efficacy of BGJ398 (infigratinib) in FGFR1-3 translocated, mutated, or amplified squamous cell carcinoma of the head and neck. Available from: https://clinicaltrials.gov/ProvidedDocs/91/NCT 02706691/Prot_SAP_000.pdf
[21]
Javle, M.; Lowery, M.; Shroff, S.T.; Weiss, k.H.; Springfeld, C.; Borad, M.J.; Ramanathan, R.K.; Goyal, L.; Sadeghi, S.; Macarulla, T.; El-Khoueiry, A.; Kelley, R.K.; Borbath, I.; Choo, S.P. Do-Youn Oh.; Philip, P.A; Chen, L.T.; Reungwetwattana, T.; Cutsem, E.V.; Yeh, K-H.; Ciombor, K.; Finn, R.S.; Patel, A.; Sen, S.; Porter, D.; Isaacs, R.; Zhu, A.X.; Abou-Alfa, G.K.; Bekaii-Saab, T. Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma. Clin. Oncol., 2018, 36(3), 276-282.
[http://dx.doi.org/10.1200/JCO.2017.75.5009] [PMID: 29182496]
[22]
Guagnano, V.; Furet, P.; Spanka, C.; Bordas, V.; Le Douget, M.; Stamm, C.; Brueggen, J.; Jensen, M.R.; Schnell, C.; Schmid, H.; Wartmann, M.; Berghausen, J.; Drueckes, P.; Zimmerlin, A.; Bussiere, D.; Murray, J.; Graus, P.D. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J. Med. Chem., 2011, 54(20), 7066-7083.
[http://dx.doi.org/10.1021/jm2006222] [PMID: 21936542]
[23]
Wermuth, C.G.; Ganellin, C.R.; Lindberg, P.; Mitscher, L.A. Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998). Pure Appl. Chem., 1998, 5, 1129-1143.
[http://dx.doi.org/10.1351/pac199870051129]
[24]
Dassault Systèmes, BIOVIA In: Discovery Studio, 4.1; Dassault Systèmes: San Diego, 2017.
[25]
Chemical Structure Drawing Standard; Cambridge Soft Corporation: USA, 2010.
[26]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[27]
Available from: . https://www.rcsb.org/
[28]
Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model., 2005, 45(1), 160-169.
[http://dx.doi.org/10.1021/ci049885e] [PMID: 15667141]
[29]
Rogers, D.; Hopfinger, A.J. Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships. J. Chem. Inf. Comput. Sci., 1994, 34, 854.
[http://dx.doi.org/10.1021/ci00020a020]
[30]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[31]
Available from: . https://www.alfa.com/en/maybridge-pre-plated-screening-compounds-and-fragment-libraries
[32]
Kabsch, W. A discussion of the solution for the best rotation to relate two sets of vectors. Acta Crystallogr., 1978, A34, 827-828.
[http://dx.doi.org/10.1107/S0567739478001680]
[33]
Diller, D.J.; Merz, K.M., Jr High throughput docking for library design and library prioritization. Proteins, 2001, 43(2), 113-124.
[http://dx.doi.org/10.1002/1097-0134(20010501)43:2<113:AID-PROT1023>3.0.CO;2-T] [PMID: 11276081]
[34]
Diller, D.J.; Li, R. Kinases, homology models, and high throughput docking. J. Med. Chem., 2003, 46(22), 4638-4647.
[http://dx.doi.org/10.1021/jm020503a] [PMID: 14561083]
[35]
Rao, S.N.; Head, M.S.; Kulkarni, A.; LaLonde, J.M. Validation studies of the site-directed docking program LibDock. J. Chem. Inf. Model., 2007, 47(6), 2159-2171.
[http://dx.doi.org/10.1021/ci6004299] [PMID: 17985863]
[36]
Kurogi, Y.; Güner, O.F. Pharmacophore modeling and three-dimensional database searching for drug design using catalyst. Curr. Med. Chem., 2001, 8(9), 1035-1055.
[http://dx.doi.org/10.2174/0929867013372481] [PMID: 11472240]
[37]
Brooks, B.R.; Bruccoleri, R.E.; Olafson, B.D.; States, D.J.; Swaminathan, S.; Karplus, M. CHARMm: A program for macromolecular energy minimization and dynamics calculations. J. Comput. Chem., 1983, 4, 187-217.
[http://dx.doi.org/10.1002/jcc.540040211]
[38]
Gehlhaar, D.K.; Verkhivker, G.M.; Rejto, P.A.; Sherman, C.J.; Fogel, D.B.; Fogel, L.J.; Freer, S.T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem. Biol., 1995, 2(5), 317-324.
[http://dx.doi.org/10.1016/1074-5521(95)90050-0] [PMID: 9383433]
[39]
Tirado-Rives, J.; Jorgensen, W.L. Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. J. Med. Chem., 2006, 49(20), 5880-5884.
[http://dx.doi.org/10.1021/jm060763i] [PMID: 17004703]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy