Molecular Modelling Studies of Ketopiperazines Steroidal Mimetics as Dual Modulators on Androgen Receptor (AR) and 17α-hydroxylase/17,20liase (CYP17)

JAVIER EIRAS; PAU ARROYO MAÑEZ; LAUTARO D. ÁLVAREZ; ANDREA C. BRUTTOMESSO

Santiago

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists; 2014

World Association of Theoretical and Computational Chemists

The main androgens are testosterone and dihydrotestosterone, and lowering their level or avoiding them from reaching cells often makes cancers shrink or grow more slowly. In this sense, AR is one of the targets to produce this result. Other important target is CYP17, which is involved in the biosynthesis of androgens. So, generating synthetic compounds with AR or/and CYP17 inhibitory activity are useful strategy in this way. Recently, crystallography structure of CYP17 was described, and proteins models are now accessible in both cases for molecular modelling. In our research group we found that 1,4-disubstituted 5-2-ketopiperazinas (KP) are CYP17 inhibitors and have action on the transcriptional activity of the AR. Therefore, this work aims to study the interactions of such compounds with these proteins in order to design new structures with improved activity. Here we study the possible conformations adopted by the compounds with computational techniques (docking and molecular dynamics (MD)) to understand the molecular determinants that govern the observed activity of these ligands. Since our compounds are substrate mimetics of the steroidal inhibitors of CYP17 and AR, crystallized structure of CYP17 in presence of abiraterone (PDB ID: 3RUK) was used as binding mode model. Docking simulations of abiraterone over CYP17 present similar conformations than the described in the reported structure. These conformations were tested by MD simulations and then, in order to compare the results with the model, docking calculations and MD simulations were carried out with compounds of highest activity (1 and 2). The MD results showed several hydrogen bond interactions that provide great stability to the ligands close to heme group of CYP17. Finally, similar strategy was used to evaluate the activity of 2 and 3 over AR. Since testosterone is the natural ligand of AR, this system was used as model (PDB ID: 2AM9). Similarly to testosterone [3], the results obtained for 3 show strong and stable hydrogen bonds between the ligand and the residues GLN 711, ARG 752 and THR 877 of AR. Additionally, the binding energy was calculated with MMPBSA calculation.