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

Kaczor AA, Targowska-Duda KM, Patel JZ, Laitinen T, Parkkari T, Adams Y, Nevalainen TJ, Poso A - J Mol Model (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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, agnieszka.kaczor@umlub.pl.

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: 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.

No MeSH data available.


The docking poses of 1 (a, b) and 6 (c, d) in the binding pocket of ABHD6 selected for molecular alignment. a, c Overview of the complex; b, d details of the binding pocket
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Fig2: The docking poses of 1 (a, b) and 6 (c, d) in the binding pocket of ABHD6 selected for molecular alignment. a, c Overview of the complex; b, d details of the binding pocket

Mentions: Homology models of ABHD6 were previously successfully applied to the molecular docking of inhibitors [19, 25]. Compounds 1–42 were thus all docked into the binding site of human ABHD6. Among the Glide docking poses, those in which the carbonyl group interacted with Phe80 were selected and used for molecular alignment. The final binding poses of compounds 1 (the most active compound) and 6 (the most promising compound from our previous article [19]) are presented in Fig. 2. It can be seen that the catalytic triad of ABHD6 comprises Ser148–His306–Asp278, and the oxyanion hole is formed by Met149 and Phe80 [19]. The most important inhibitor contact is a hydrogen bond between the carbonyl group of the ligand and the main chain of Phe80.Fig. 2


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

Kaczor AA, Targowska-Duda KM, Patel JZ, Laitinen T, Parkkari T, Adams Y, Nevalainen TJ, Poso A - J Mol Model (2015)

The docking poses of 1 (a, b) and 6 (c, d) in the binding pocket of ABHD6 selected for molecular alignment. a, c Overview of the complex; b, d details of the binding pocket
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4562993&req=5

Fig2: The docking poses of 1 (a, b) and 6 (c, d) in the binding pocket of ABHD6 selected for molecular alignment. a, c Overview of the complex; b, d details of the binding pocket
Mentions: Homology models of ABHD6 were previously successfully applied to the molecular docking of inhibitors [19, 25]. Compounds 1–42 were thus all docked into the binding site of human ABHD6. Among the Glide docking poses, those in which the carbonyl group interacted with Phe80 were selected and used for molecular alignment. The final binding poses of compounds 1 (the most active compound) and 6 (the most promising compound from our previous article [19]) are presented in Fig. 2. It can be seen that the catalytic triad of ABHD6 comprises Ser148–His306–Asp278, and the oxyanion hole is formed by Met149 and Phe80 [19]. The most important inhibitor contact is a hydrogen bond between the carbonyl group of the ligand and the main chain of Phe80.Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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, agnieszka.kaczor@umlub.pl.

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: 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.

No MeSH data available.