title: Re-emergence of an orphan therapeutic target for the treatment of resistant prostate cancer - a thorough conformational and binding analysis for ROR-γ protein.
abstract: Recent studies have linked a deadly form of prostate cancer known as metastatic castration-resistant prostate cancer to retinoic acid-related orphan-receptor gamma (ROR-γ). Most of these studies continued to place ROR-γ as orphan because of unidentifiable inhibitor. Recently identified inhibitors of ROR-γ and their therapeutic potential were evaluated, among which inhibitor XY018 was the potent. However, molecular understanding of the conformational features of XY018-ROR-γ complex is still elusive. Herein, molecular dynamics simulations were conducted on HC9-ROR-γ and XY018-ROR-γ complexes to understand their conformational features at molecular level and the influence of XY018 binding on the dynamics of ROR-γ with the aid of post-dynamic analytical tools. These include; principal component analysis, radius of gyration, binding free energy calculation (MM/GBSA), per-residue fluctuation and hydrogen bond occupancy. Findings from this study revealed that (1) hydrophobic packing contributes significantly to binding free energy, (2) Ile136 and Leu60 exhibited high hydrogen-bond occupancy in XY018-ROR-γ and HC9-ROR-γ, respectively, (3) XY018-ROR-γ displayed a relatively high loop region residue fluctuation compared to HC9-ROR-γ, (4) electrostatic interactions are a potential binding force in XY018-ROR-γ complex compared to HC9-ROR-γ, (5) XY018-ROR-γ assumes a rigid conformation which is highlighted by a decrease in residual fluctuation, (6) XY018 could potentially induce pseudoporphyria, nephritis and interstitial nephritis but potentially safe in renal failure. This study could serve as a base line for the design of new potential ROR-γ inhibitors.
authors.affiliation: a Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal , Westville , Durban 4000 , South Africa.
authors.forename: Umar
authors.initials: U
authors.lastname: Ndagi
authors.affiliation: a Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal , Westville , Durban 4000 , South Africa.
authors.forename: Ndumiso N
authors.initials: NN
authors.lastname: Mhlongo
authors.affiliation: a Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal , Westville , Durban 4000 , South Africa.
authors.forename: Mahmoud E
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008968:Molecular Conformation / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D046911:Macromolecular Substances; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma
keywords: PCA; ROR-γ; binding free energy and MD; cancer