Computational Analysis of Residue-Specific Binding Free Energies of Androgen Receptor to Ligands

Abstract

Androgen receptor (AR) is an important therapeutic target for the treatment of diseases such as prostate cancer, hypogonadism, muscle wasting, etc. In this study, the complex structures of the AR ligand-binding domain (LBD) with fifteen ligands were analyzed by molecular dynamics simulations combined with the alanine-scanning-interaction-entropy method (ASIE). The quantitative free energy contributions of the pocket residues were obtained and hotspot residues are quantitatively identified. Our calculation shows that that these hotspot residues are predominantly hydrophobic and their interactions with binding ligands are mainly van der Waals interactions. The total binding free energies obtained by summing over binding contributions by individual residues are in good correlation with the experimental binding data. The current quantitative analysis of binding mechanism of AR to ligands provides important insight on the design of future inhibitors.

Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer

“…Our simulations have shown that residues involved in the binding of those small molecules (e.g., T603, K610, R611) sampled a series of different configurational states through the nanoseconds to microseconds timescale, which is likely to contribute to the relatively low affinities of the compound (e.g., K i within µM range reported for pyrvinium) [ 22 ]. Challenges of direct DBD targeting rendered the LBD a more attractive binding site for small molecules, given its reported allosteric sites and highly conserved orthosteric pocket [ 24 , 25 , 26 , 27 ]. However, AR mutants lacking LBD (e.g., ARV7; exon 4 deletion), which remain functional receptors yet insensitive to inhibitors targeting LBD, are the leading cause of drug resistance.…”

Molecular investigation of the dual inhibition mechanism for targeted P53 regulator MDM2/MDMX inhibitors

“…MM/GBSA is a common method for calculating enthalpic contribution. 76–81 Its basic principle is the conversion of the enthalpy change into the sum of the gas-phase free energy (Δ G gas ) and solvation free energy (Δ G sol ):Δ H = Δ G gas + Δ G sol …”