Identification of terpenoids from Withania somnifera as a HIV-1 entry inhibitors that prevent gp120 binding to CD4 using In Silico Approach

Introduction Human immunodeficiency virus (HIV-1), the most prevalent and pathogenic type of the virus, is what causes acquired immunodeficiency syndrome (AIDS). Approximately 30 anti-HIV-1 medications have been applied to the management of AIDS. However, effective anti HIV-1 agents with less side affect and high inhibition potency are still in demand. The objective of this study was to identify the potential terpenoid compounds from Withania somnifera plant that might be active as anti-HIV-1 gp120 by molecular docking that inhibits viral attachment and entry for the treatment of HIV/AIDS patients. In this investigation we have performed molecular docking, to develop a novel anti‑HIV drug. We have screened 12 terpenoids from a medicinal plant Withania somnifera for its probabilistic binding with the active site of the HIV‑1 gp120 domain the major contributor to the onset of the disease. The docking results were evaluated based on free energies of binding (∆G), and the results suggested withasomidienone, 2,3-didehydrosomnifericin, withasomniferol B, amyrin and 24,25-dihydrowithanolide D to be potent inhibitors of HIV‑1 gp120. These scores were comparable with the standard BMS-378806 drug. The docking molecular study has identified the possible potential terpenoids compounds from Withania somnifera plant that might be used for anti-HIV-1 treatment. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics. Keywords: Human immunodeficiency virus‑1 gp120, Terpenoids, Molecular docking REFERENCES Bhakta D, Siva R. Morindone, an anthraquinone, intercalates DNA sans toxicity: A spectroscopic and molecular modeling perspective. Appl Biochem Biotechnol 2012;167:885‑96. Chen W, Zhan P, De CE, Liu X. Recent progress in small molecule CCR5 antagonists as potential HIV-1 entry inhibitors. Curr Pharm Des. 2012;18(1):100–112. Davella R, Gurrapu S, Mamidala E. Phenolic compounds as promising drug candidates against COVID-19 - an integrated molecular docking and dynamics simulation study. Mater Today Proc.2022;51:522-527. https://10.1016/j.matpr.2021.05.595 Jarrahpour A, Fathi J, Mimouni M, Hadda TB, Sheikh J, Chohan Z, et al. Petra, Osiris and Molinspiration (POM) together as a successful support in drug design: Antibacterial activity and biopharmaceutical characterization of some azo schiff bases. Med Chem Res 2012;21:1‑7. Judith M. LaLonde, Young Do Kwon, David M. Jones, Alexander W. Sun, Joel R. Courter, Takahiro Soeta,§ Toyoharu Kobayashi, Amy M. Princiotto, Xueling Wu, Arne Schö n, Ernesto Freire, Peter D. Kwong, John R. Mascola, Joseph Sodroski, Navid Madani, and Amos B. Smith, III Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry. .J. Med. Chem. 2012, 55, 4382−4396. https://dx.doi.org/10.1021/jm300265j. Kuboyam A T, Tohda C, Komatsu K. Withanoside IV and its active metabolite, sominone, attenuate A beta(25–35)-induced neurodegeneration. Eur J Neurosci. 2006;23(6):1417–1426. Kwon YD, Finzi A, Wu X, Dogo-Isonagie C, Lee LK, Moore LR, Schmidt SD, Stuckey J, Yang Y, Zhou T, Zhu J, Vicic DA, Debnath AK, Shapiro L, Bewley CA, Mascola JR, Sodroski JG, Kwong PD. Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci U S A. 2012;109(15):5663–5668 Lombardi S, Massi C, Indino E, La Rosa C, Mazzetti P, Falcone ML, Rovero P, Fissi A, Pieroni O, Bandecchi P, Esposito F, Tozzini F, Bendinelli M, Garzelli C. Inhibition of feline immunodeficiency virus infection in vitro by envelope glycoprotein synthetic peptides. Virology. 1996;220(2):274–284. Mamidala, E., Davella, R., Gurrapu, S., and Shivakrishna, P. 2020. In silico identification of clinically approved medicines against the main protease of SARS-CoV-2, causative agent of covid-19. arXiv:2004.12055v1. Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera. (Ashwagandha): A review. Alternative Medicine Reviews. 2000;5:334–346. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30:2785‑91. Wang T, Kadow JF, Zhang Z, Yin Z, Gao Q, Wu D, et al. Bioorganic & Medicinal Chemistry Letters Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives q. Bioorg Med Chem Lett. 2009;19(17):5140–5. World Health Organization. (Accessed 02 November 2021). https://www.who.int/news-room/fact-sheets/detail/hiv-aids