IDENTIFYING POTENTIAL hENR INHIBITORS AGAINST PROSTATE CANCER EMPLOYING IN SILICO DRUG REPURPOSING APPROACH

KAVANA KRISHNA NAYAK; SUMIT RAOSAHEB BIRANGAL; LALIT  KUMAR; RUCHI VERMA

doi:10.22159/ijap.2024v16i6.51700

Authors

KAVANA KRISHNA NAYAK Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India https://orcid.org/0009-0008-1456-2828
SUMIT RAOSAHEB BIRANGAL Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
LALIT KUMAR Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hajipur, India https://orcid.org/0000-0002-2418-9712
RUCHI VERMA Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India https://orcid.org/0000-0002-1279-7243

DOI:

https://doi.org/10.22159/ijap.2024v16i6.51700

Keywords:

Prostate cancer, hENR, Docking, In silico, Molecular dynamics simulation, Drug repurposing

Abstract

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

Download data is not yet available.

References

Mouchati C, Abdallah N, Jani C, Mariano M, Jani RT, Marshall DC. Trends in disease burden from prostate cancer amongst different regions of the world and extensively the European Union 15+ countries from 1990 to 2019: estimates from the global burden of disease study. J Clin Oncol. 2022;40 Suppl 6:187. doi: 10.1200/JCO.2022.40.6_suppl.187.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A. 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):209-49. doi: 10.3322/caac.21660, PMID 33538338.

Giona S. The epidemiology of prostate cancer Bott SR Ng KL, editors. Brisbane: Exon Publications; 2021. p. 1-17.

Perez Herrero E, Fernandez 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. 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 Sep 5;834:188-96. 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: 10.1016/j.jons.2017.06.002.

Chen Y, LI P. Fatty acid metabolism and cancer development. Science Bulletin. 2016;61(19):1473-9. doi: 10.1007/s11434-016-1129-4.

Galbraith L, Leung HY, Ahmad I. Lipid pathway deregulation in advanced prostate cancer. Pharmacol Res. 2018;131:177-84. 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. Exploring a role for fatty acid synthase in prostate cancer cell migration. Small GTPases. 2021;12(4):265-72. doi: 10.1080/21541248.2020.1826781, PMID 33043786.

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, PMID 25301948, 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 parkinsons disease by integrating knowledge graph completion model and knowledge fusion of medical literature. Future Internet. 2021;13(1):14. doi: 10.3390/fi13010014.

Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A. Drug repurposing: progress challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41-58. doi: 10.1038/nrd.2018.168, PMID 30310233.

Honkisz E, Zieba Przybylska D, Wojtowicz AK. The effect of triclosan on hormone secretion and viability of human choriocarcinoma JEG-3 cells. Reprod Toxicol. 2012;34(3):385-92. doi: 10.1016/j.reprotox.2012.05.094, 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 Pharmacol Toxicol. 2012;110(6):494-503. doi: 10.1111/j.1742-7843.2011.00844.x, PMID 22151915.

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 TR, Varkey J, Varkey J. Antioxidant anticancer and molecular docking studies of novel 5-benzylidene substituted rhodanine derivatives. Int J Pharm Pharm Sci. 2023;15(7):7-19. doi: 10.22159/ijpps.2023v15i7.47421.

Verma R, Boshoff HI, Arora K, Bairy I, Tiwari M, Varadaraj BG. 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):315-28. 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;15(7):e0235030. doi: 10.1371/journal.pone.0235030, PMID 32706783.

Parasuraman S, Raveendran R, Vijayakumar B, Velmurugan D, Balamurugan S. Molecular docking and ex vivo pharmacological evaluation of constituents of the leaves of Cleistanthus collinus (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):541-54. 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 Alzheimers disease. BMC Neurosci. 2017;18(1):76. doi: 10.1186/s12868-017-0394-8, PMID 29078760.

Harshitha T, Vinak KT, 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;14(4):74-7. doi: 10.22159/ijcpr.2022v14i4.2001.

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. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorg Med Chem Lett. 2018;28(12):2195-200. doi: 10.1016/j.bmcl.2018.05.003, PMID 29764741.

Chintha C, Carlesso A, Gorman AM, Samali A, Eriksson LA. Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1. RSC Adv. 2019;10(1):367-75. doi: 10.1039/c9ra08047c, PMID 35558862.

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.