Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors.

Agnieszka A Kaczor,Teija Parkkari,Yahaya Adams,Jayendra Z Patel,Tuomo Laitinen,Katarzyna M Targowska-Duda,Antti Poso,Tapio J Nevalainen

doi:10.1007/s00894-015-2789-8

Abstract

The endocannabinoid system remains an attractive molecular target for pharmacological intervention due to its roles in the central nervous system in learning, thinking, emotional function, regulation of food intake or pain sensation, as well as in the peripheral nervous system, where it modulates the action of cardiovascular, immune, metabolic or reproductive function. α/β hydrolase domain containing 6 (ABHD6)—an enzyme forming part of the endocannabinoid system—is a newly discovered post-genomic protein acting as a 2-AG (2-arachidonoylglycerol) serine hydrolase. We have recently reported a series of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. Here, we present comparative molecular field analysis (CoMFA) and molecular dynamics studies of these compounds. First, we performed a homology modeling study of ABHD6 based on the assumption that the catalytic triad of ABHD6 comprises Ser148–His306–Asp 278 and the oxyanion hole is formed by Met149 and Phe80. A total of 42 compounds was docked to the homology model using the Glide module from the Schrödinger suite of software and the selected docking poses were used for CoMFA alignment. A model with the following statistics was obtained: R2 = 0.98, Q2 = 0.55. In order to study the molecular interactions of the inhibitors with ABHD6 in detail, molecular dynamics was performed with the Desmond program. It was found that, during the simulations, the hydrogen bond between the inhibitor carbonyl group and the main chain of Phe80 is weakened, whereas a new hydrogen bond with the side chain of Ser148 is formed, facilitating the possible formation of a covalent bond.Graphical Left–right: Docking pose of 1 in the binding pocket of α/β hydrolase domain containing 6 (ABHD6) selected for molecular alignment; CoMFA steric and electrostatic contour fields; changes in potential energy of the complex during simulations for the complex of 6 and ABHD6Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-015-2789-8) contains supplementary material, which is available to authorized users.

Highlights

The endocannabinoid signaling system (ECS) regulates diverse physiological processes and has attracted significant attention as a potential drug target [1]
In spite of successful attempts to construct homology models of ABHD6 [19, 25], and to use molecular docking to build complexes with inhibitors, no molecular dynamics (MD) studies have been reported for this enzyme
We have recently developed a series of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors [19]

Summary

Introduction

The endocannabinoid signaling system (ECS) regulates diverse physiological processes and has attracted significant attention as a potential drug target [1]. 3D-QSAR approaches, including comparative molecular field analysis (CoMFA) [21] and comparative molecular similarity index analysis (CoMSIA) [22] make an important contribution to drug design through deriving structural information in interactive fields and predicting the influence on activity [23]. To the best of our knowledge, our study is the first attempt to develop a CoMFA model for ABHD6 inhibitors.

Results

Conclusion