title: Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists.
abstract: The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Han
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Jiazhong
authors.identifier: 0000-0003-2437-4675
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou 730000, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Theoretical and Applied Sciences, University of Insubria, Via Dunant 3, 21100 Varese, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gramatica
mesh_terms: D000465:Algorithms; D059002:Androgen Receptor Antagonists / Q000737:chemistry; D019295:Computational Biology; D013196:Dihydrotestosterone / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D016014:Linear Models; D008297:Male; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011467:Prostate / Q000473:pathology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011944:Receptors, Androgen / Q000737:chemistry*; D013256:Steroids / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D008024:Ligands; D011944:Receptors, Androgen; D013256:Steroids; D013196:Dihydrotestosterone