caa a22 4500 605512124 CHVBK 20210128100654.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00894-015-2789-8 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2789-8 Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors [Elektronische Daten] [Agnieszka Kaczor, Katarzyna Targowska-Duda, Jayendra Patel, Tuomo Laitinen, Teija Parkkari, Yahaya Adams, Tapio Nevalainen, Antti Poso] 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: R 2=0.98, Q 2=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 Abstract 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 ABHD6 The Author(s), 2015 ABHD6 nationallicence ABHD6 inhibitors nationallicence CoMFA nationallicence The endocannabinoid system nationallicence Homology modeling nationallicence Molecular docking nationallicence Molecular dynamics nationallicence 2-AG : 2-Arachidonoylglycerol nationallicence ABHD6 : α/β Hydrolase domain containing 6 nationallicence ABHD12 : α/β Hydrolase domain containing 12 nationallicence ANN : Artificial neural network nationallicence CB1 : Cannabinoid receptor 1 nationallicence CB2 : Cannabinoid receptor 2 nationallicence CoMFA : Comparative molecular field analysis nationallicence CoMSIA : Comparative molecular similarity index analysis nationallicence DSE : Depolarization-induced suppression of excitation nationallicence DSI : Depolarization-induced suppression of inhibition nationallicence ECS : Endocannabinoid signaling system nationallicence G/PLS : Genetic partial least squares nationallicence LOO : Leave-one-out nationallicence MD : Molecular dynamics nationallicence MGL : Monoacylglycerol lipase nationallicence ONC : Optimum number of components nationallicence PLS : Partial least squares nationallicence QSAR : Quantitative structure-activity relationship nationallicence SEE : Standard error of estimation nationallicence Kaczor Agnieszka Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Molecular Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland aut Targowska-Duda Katarzyna Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland aut Patel Jayendra School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Laitinen Tuomo School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Parkkari Teija School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Adams Yahaya School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Nevalainen Tapio School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Poso Antti School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-16 1610-2940 21:10<1 2015 21 894 https://doi.org/10.1007/s00894-015-2789-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2789-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kaczor Agnieszka Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Molecular Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland aut NATIONALLICENCE 700 1- Targowska-Duda Katarzyna Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland aut NATIONALLICENCE 700 1- Patel Jayendra School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 700 1- Laitinen Tuomo School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 700 1- Parkkari Teija School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 700 1- Adams Yahaya School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 700 1- Nevalainen Tapio School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 700 1- Poso Antti School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-16 1610-2940 21:10<1 2015 21 894