Phytochemicals of Withania coagulans (Stocks) Dunal against androgen receptor: An in silico insight

Objectives: The androgen receptor is considered a magic target due to its involvement in multiple pathways leading to several maladies and its accessibility for small molecules to bind to it and modulate its normal functioning.The phytochemicals from the plant, Withania coagulans (Stocks) Dunal (common name: Rishyagandha) with traditional practice in healing different diseases were investigated in this regard.The higher safety profile and cost-effective features of plant-based resources in the design and development of drug like candidates seems to be worthy of exploration in the realm of alternate therapeutic options.Methods: Several computational methods involving flexible receptor molecular docking calculations and molecular dynamics simulations were carried out.Spatially and thermodynamically stable adducts with best docking scores were identified using various parameters extracted from the molecular dynamics trajectory to find the hit candidates capable of inhibiting or disrupting the normal functioning of the target protein leading to the cure of the disease.The server based ADMET prediction was performed to comprehend the druglikeness, bioavailability, and toxicity profile of different phytochemicals.Results: The molecule, 24-Methyl-9,19-cyclolanost-25-en-3-ol (PubChem CID: 185036) showed the binding score of -10.726 kcal/mol against androgen receptor (PDB ID: 1E3G) better than that of the native ligand, 17--hydroxy-17-methylestra-4,9,11-trien-3-one (PubChem CID: 261000) with -10.268 kcal/mol and selected anticancer drugs (best value of -10.080 kcal/mol for darolutamide).Withacoagulin I (PubChem CID: 71720665) displayed the binding score of -10.108 kcal/mol and was considered the second top molecule.The stability of the protein-phytochemical adducts as calculated from 200 ns long molecular dynamics simulations revealed good geometrical intactness from multiple spatial descriptors (root mean square deviation, radial pair distribution function, and hydrogen bond distribution) and sustained thermodynamical spontaneity from binding free energy changes of the protein-ligand complexes.The pharmacokinetics and pharmacodynamics showed acceptable druglike properties, good bioavailability and safety comparable with that of the reference drugs.Conclusions: The hit molecules could be considered as possibly capable of inhibiting the target protein that would perform as anticancer agents and are recommended for further experimental trials for the verification of theoretical inferences.