Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors
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| 024 | 7 | 0 | |a 10.1007/s00894-015-2789-8 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00894-015-2789-8 | ||
| 245 | 0 | 0 | |a Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors |h [Elektronische Daten] |c [Agnieszka Kaczor, Katarzyna Targowska-Duda, Jayendra Patel, Tuomo Laitinen, Teija Parkkari, Yahaya Adams, Tapio Nevalainen, Antti Poso] |
| 520 | 3 | |a 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 | |
| 540 | |a The Author(s), 2015 | ||
| 690 | 7 | |a ABHD6 |2 nationallicence | |
| 690 | 7 | |a ABHD6 inhibitors |2 nationallicence | |
| 690 | 7 | |a CoMFA |2 nationallicence | |
| 690 | 7 | |a The endocannabinoid system |2 nationallicence | |
| 690 | 7 | |a Homology modeling |2 nationallicence | |
| 690 | 7 | |a Molecular docking |2 nationallicence | |
| 690 | 7 | |a Molecular dynamics |2 nationallicence | |
| 690 | 7 | |a 2-AG : 2-Arachidonoylglycerol |2 nationallicence | |
| 690 | 7 | |a ABHD6 : α/β Hydrolase domain containing 6 |2 nationallicence | |
| 690 | 7 | |a ABHD12 : α/β Hydrolase domain containing 12 |2 nationallicence | |
| 690 | 7 | |a ANN : Artificial neural network |2 nationallicence | |
| 690 | 7 | |a CB1 : Cannabinoid receptor 1 |2 nationallicence | |
| 690 | 7 | |a CB2 : Cannabinoid receptor 2 |2 nationallicence | |
| 690 | 7 | |a CoMFA : Comparative molecular field analysis |2 nationallicence | |
| 690 | 7 | |a CoMSIA : Comparative molecular similarity index analysis |2 nationallicence | |
| 690 | 7 | |a DSE : Depolarization-induced suppression of excitation |2 nationallicence | |
| 690 | 7 | |a DSI : Depolarization-induced suppression of inhibition |2 nationallicence | |
| 690 | 7 | |a ECS : Endocannabinoid signaling system |2 nationallicence | |
| 690 | 7 | |a G/PLS : Genetic partial least squares |2 nationallicence | |
| 690 | 7 | |a LOO : Leave-one-out |2 nationallicence | |
| 690 | 7 | |a MD : Molecular dynamics |2 nationallicence | |
| 690 | 7 | |a MGL : Monoacylglycerol lipase |2 nationallicence | |
| 690 | 7 | |a ONC : Optimum number of components |2 nationallicence | |
| 690 | 7 | |a PLS : Partial least squares |2 nationallicence | |
| 690 | 7 | |a QSAR : Quantitative structure-activity relationship |2 nationallicence | |
| 690 | 7 | |a SEE : Standard error of estimation |2 nationallicence | |
| 700 | 1 | |a Kaczor |D Agnieszka |u 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 |4 aut | |
| 700 | 1 | |a Targowska-Duda |D Katarzyna |u Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland |4 aut | |
| 700 | 1 | |a Patel |D Jayendra |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 700 | 1 | |a Laitinen |D Tuomo |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 700 | 1 | |a Parkkari |D Teija |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 700 | 1 | |a Adams |D Yahaya |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 700 | 1 | |a Nevalainen |D Tapio |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 700 | 1 | |a Poso |D Antti |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | |
| 773 | 0 | |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/10(2015-10-01), 1-16 |x 1610-2940 |q 21:10<1 |1 2015 |2 21 |o 894 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00894-015-2789-8 |q text/html |z Onlinezugriff via DOI |
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| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
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| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00894-015-2789-8 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kaczor |D Agnieszka |u 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 |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Targowska-Duda |D Katarzyna |u Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4a Chodźki St., 20059, Lublin, Poland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Patel |D Jayendra |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Laitinen |D Tuomo |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Parkkari |D Teija |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Adams |D Yahaya |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Nevalainen |D Tapio |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Poso |D Antti |u School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/10(2015-10-01), 1-16 |x 1610-2940 |q 21:10<1 |1 2015 |2 21 |o 894 | ||