IDENTIFYING POTENTIAL HENR INHIBITORS AGAINST PROSTATE CANCER EMPLOYING IN SILICO DRUG REPURPOSING APPROACH
DOI:
https://doi.org/10.22159/ijap.2024v16i6.51700Keywords:
Prostate cancer, hENR, Docking, In silico, Molecular dynamics simulation, Drug repurposingAbstract
Objective: This study employed an in-silico drug repurposing strategy to identify potential human enoyl acyl carrier protein reductase (hENR) inhibitors.
Methods: The co-crystallized ligand triclosan was used as a reference standard. Initially, FDA-approved drugs from the Drug Bank database were docked against the hENR and compounds with appreciable binding affinities with the protein were shortlisted. The binding energy calculations, ADME analysis, and induced-fit docking results of shortlisted compounds led to the identification of two top hits, DB07676 and DB11399, which were further subjected to molecular dynamics simulation.
Results: Of 2,509 ligands docked via High Throughput Virtual Screening (HTVS), the top 250 were assessed with Standard Precision (SP) and the top 25 with Extra Precision (XP) mode. Thirteen compounds were selected based on interactions and XP scores, ranging from -15.245 to -10.031. Relative binding free energies of ligands DB07676 and DB11399 were -54.18 and -61.38 kcalmol-1, respectively. ADME analysis confirmed that both ligands followed Lipinski's Rule, though DB11399 had a high log P, which could be addressed by adding polar groups. Induced Fit scores for DB07676 and DB11399 were -10.592 and -11.220, respectively. Molecular Dynamics simulations confirmed superior stability of these complexes with RMSD ranging from 1.2 to 3.5 Å for the protein and 1.7 to 5.2 Å for the ligand with DB07676-protein complex and 1.4 to 3.0 Å for the protein and 1.1 to 5.8 Å for the ligand with DB11399-protein complex.
Conclusion: Our final findings suggested that DB07676 and DB11399 could be potential lead compounds as hENR inhibitors.
Downloads
References
Mouchati C, Abdallah N, Jani C, Melissa M., Ruchi T.J, Dominic C.M., Harpreet S., Joseph S., Justin S., Rana R. McKayTrends in disease burden from prostate cancer amongst different regions of the worldand extensively the European Union 15+ countries, from 1990 to2019: estimates from the global burden of disease study. J Clin.Oncol. 2022; 40:187. https://doi.org/10.1200/JCO.2022.40.6_suppl.18
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. PMID: 33538338.
GionaS.The epidemiology of prostate cancer, S.R.J. Bott, K.L.Ng, eds. , Exon Publications, Brisbane, 2021, pp. 1-17.
Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm. 2015;93:52-79. doi: 10.1016/j.ejpb.2015.03.018. PMID: 25813885.
Nawaz K, Webster RM. The non-small-cell lung cancer drug market. Nat Rev Drug Discov. 2016;15(4):229-30. doi: 10.1038/nrd.2016.42. PMID: 27032828.
Ali R, Mirza Z, Ashraf GM, Kamal MA, Ansari SA, Damanhouri GA, Abuzenadah AM, Chaudhary AG, Sheikh IA. New anticancer agents: recent developments in tumor therapy. Anticancer Res. 2012;32(7):2999-3005. PMID: 22753764.
Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol. 2018;834:188-196. doi: 10.1016/j.ejphar.2018.07.034. PMID: 30031797.
Fadaka A, Ajiboye B, Ojo O, Adewale O, Olayide I, Emuowhochere R. Biology of glucose metabolization in cancer cells. J Oncol Sci. 2017;3(2):45–51.doi: http://dx.doi.org/10.1016/j.jons.2017.06.002.
Chen Y, Li P. Fatty acid metabolism and cancer development. Sci Bull. 2016;61(19):1473–9. doi: http://dx.doi.org/10.1007/s11434-016-1129-4.
Galbraith L, Leung HY, Ahmad I. Lipid pathway deregulation in advanced prostate cancer. Pharmacol Res. 2018;131:177-184. doi: 10.1016/j.phrs.2018.02.022.PMID: 29466694.
Liu H, Liu JY, Wu X, Zhang JT. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int J Biochem Mol Biol. 2010;1(1):69-89. PMID: 20706604.
De Piano M, Manuelli V, Zadra G, Loda M, Muir G, Chandra A, Morris J, Van Hemelrijck M, Wells CM. Exploring a role for fatty acid synthase in prostate cancer cell migration. Small GTPases. 2021;12(4):265-272. doi: 10.1080/21541248.2020.1826781.
Sippel KH, Vyas NK, Zhang W, Sankaran B, Quiocho FA. Crystal structure of the human fatty acid synthase enoyl-acyl carrier protein-reductase domain complexed with triclosan reveals allosteric protein-protein interface inhibition. J Biol Chem. 2014;289(48):33287-95. doi: 10.1074/jbc.M114.608547.PMCID: PMC4246086.
Maier T, Leibundgut M, Ban N. The crystal structure of a mammalian fatty acid synthase. Science. 2008;321(5894):1315-22. doi: 10.1126/science.1161269. PMID: 18772430.
Zhang X, Che C. Drug Repurposing for Parkinson’s Disease by Integrating Knowledge Graph Completion Model and Knowledge Fusion of Medical Literature. Future Internet. 2021; 13(1):14. https://doi.org/10.3390/fi13010014
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41-58. doi: 10.1038/nrd.2018.168. Epub 2018 Oct 12. PMID: 30310233.
Honkisz E, Zieba-Przybylska D, Wojtowicz AK. The effect of triclosan on hormone secretion and viability of human choriocarcinoma JEG-3 cells. ReprodToxicol. 2012;34(3):385-92. doi: 10.1016/j.reprotox.2012.05.094. Epub 2012 Jun 4. PMID: 22677473.
Deepa PR, Vandhana S, Jayanthi U, Krishnakumar S. Therapeutic and toxicologic evaluation of anti-lipogenic agents in cancer cells compared with non-neoplastic cells. Basic Clin PharmacolToxicol. 2012;110(6):494-503. doi: 10.1111/j.1742-7843.2011.00844.x.
Lupu R, Menendez JA. Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol. 2006;7(6):483-93. doi: 10.2174/138920106779116928. PMID: 17168665.
Jays J, Saravanan J. A molecular modelling approach for structure-based virtual screening and identification of novel isoxazoles as potential antimicrobial agents against S. Aureus. Int J Pharm Pharm Sci. 2024;16(4):36-41.doi:10.22159/ijpps.2024v16i4.49731
Mathew C, Lal N, Aswathy T.R.,Varkey J. Antioxidant, anticancer and molecular docking studiesof novel 5-benzylidene substituted rhodanine derivatives. Int J Pharm Pharm Sci. 2023. 26;15(7):7-19. doi:10.22159/ijpps.2023v15i7.47421
Verma R, Boshoff HIM, Arora K, Bairy I, Tiwari M, Varadaraj BG, Shenoy GG. Synthesis, evaluation, molecular docking, and molecular dynamics studies of novel N-(4-[pyridin-2-yloxy]benzyl)arylamine derivatives as potential antitubercular agents. Drug Dev Res. 2020;81(3):315-328. doi: 10.1002/ddr.21623.PMID: 31782209.
Choudhary MI, Shaikh M, Tul-Wahab A, Ur-Rahman A. In silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation. PLoS One. 2020 24;15(7):e0235030. doi: 10.1371/journal.pone.0235030
Parasuraman S, Raveendran R, Vijayakumar B, Velmurugan D, Balamurugan S. Molecular docking and ex vivo pharmacological evaluation of constituents of the leaves of Cleistanthuscollinus (Roxb.) (Euphorbiaceae). Indian J Pharmacol. 2012;44(2):197-203. doi: 10.4103/0253-7613.93848. PMID: 22529475
Verma R, Bairy I, Tiwari M, Bhat GV, Shenoy GG. In silico studies, synthesis and anticancer activity of novel diphenyl ether-based pyridine derivatives. Mol Divers. 2019 Aug;23(3):541-554. doi: 10.1007/s11030-018-9889-1.PMID: 30430400.
Mishra H, Singh N, Lahiri T, Misra K. A comparative study on the molecular descriptors for predicting drug-likeness of small molecules. Bioinformation. 2009;3(9):384-8. doi: 10.6026/97320630003384. PMID: 19707563; PMCID: PMC2728118
Kumar S, Chowdhury S, Kumar S. In silico repurposing of antipsychotic drugs for Alzheimer's disease. BMC Neurosci. 2017;18(1):76. doi: 10.1186/s12868-017-0394-8.
Harshitha T, VinakK.T, Vineetha T. In silico characterization, molecular docking, and in vitro evaluation of triazole derivatives as potential anticancer agents. Asian J Pharm Clin Res. 2021;14(2):22-8.doi: 10.22159/ajpcr.2021.v14i2.40053
Sai GC, Jays J, Madriwala B. Design, binding affinity studies and in silico ADMET predictions of novel isoxazoles as potential anti-bacterial. Int J Curr Pharm Sci. 2022. 15;14(4):74-7.
Barreca ML, Iraci N, De Luca L, Chimirri A. Induced-fit docking approach provides insight into the binding mode and mechanism of action of HIV-1 integrase inhibitors. Chem.Med.Chem. 2009;4(9):1446-56. doi: 10.1002/cmdc.200900166. PMID: 19544345.
Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorg Med Chem Lett. 2018 ;28(12):2195-2200. doi: 10.1016/j.bmcl.2018.05.003.
Chintha C., Carlesso A., Gorman A. M., Samali A., Eriksson, L. A. Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1. RSC Adv. 2019; 10, 367–375. doi:10.1039/c9ra08047c
Sachdeo R, Khanwelkar C, Shete A. In silico exploration of berberine as a potential wound healing agent via network pharmacology, molecular docking, and molecular dynamics simulation. Int J App Pharm. 2024 ;16(2):188-94. doi:10.22159/ijap.2024v16i2.49922.
Published
How to Cite
Issue
Section
Copyright (c) 2024 KAVANA KRISHNA NAYAK, SUMIT RAOSAHEB BIRANGAL, LALIT KUMAR, RUCHI VERMA
This work is licensed under a Creative Commons Attribution 4.0 International License.