120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-330
Subject Computational studies of the structure-activity relationships of small molecular inhibitors for EGFR and androgen receptor
Authors Jiyong Park*, Ken Houk1
Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science, Korea
1Dept. of Chemistry and Biochemistry, UCLA, United States
Abstract Detailed understanding of the drug-target interaction profiles can accelerate the drug discovery process by providing guiding principles for the rational drug design. We utilize advanced molecular dynamics MD simulation techniques to quantify the binding affinity profiles and the inhibitor induced conformational changes of EGFR kinase and androgen receptor (AR). We rationalized how clinically implicated mutations of EGFR kinase modulate the potency profiles of selective inhibitors the kinase. Molecular dynamics (MD) simulations showed that the mutations influence both the conformational equilibrium and the binding affinity to the target conformation of the kinase that the inhibitors recognize. Computed binding affinity changes were in quantitative agreement with the experimental potency profiles. In addition, we studied how the binding of the inhibitors influence the conformational characteristics of the androgen receptor (AR). Previously, it was envisioned that the binding of the AR ligands induces conformational changes in the ligand binding domain, that is correlated with the activity of the ligand. The binding of enzalutamide, a selective inhibitor of AR, alters the orientation of the helix 12. On the other hand, the binding of dihydrotestosterone (DHT) did not influence the structural integrity of the ligand binding domain. Based on the computational results, we proposed a structure-activity relationship (SAR) model that explains the efficacy of the AR inhibitors.
E-mail jiyongpa@ibs.re.kr