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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.


CoMFA steric and electrostatic contour fields. Fields drawn with 85/15 proportion of favorable and unfavorable interactions. The most active compound (1) is shown
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Fig4: CoMFA steric and electrostatic contour fields. Fields drawn with 85/15 proportion of favorable and unfavorable interactions. The most active compound (1) is shown

Mentions: Figure 4 shows the steric and electrostatic contour maps generated via CoMFA modeling. Steric contour maps give information about the spatial volume of substituted groups at different positions. There were three green and one yellow contour regions located in the active site, with green meaning bulky groups are favored and yellow meaning bulky groups are disfavored. The yellow contour map may explain the lower activity of compounds 27, 28, 31, 33, 36 and 40, which have a bulky substituent in this position. Interestingly, there is a red contour region near the carbonyl group, meaning that less negative charge would be favored here. This is probably not connected with the sp2 hybridized oxygen atom but with the polarizability of the whole area. Importantly, the carbonyl group is a key moiety interacting with the active site of ABHD6 as the most important inhibitor contact is a hydrogen bond between the carbonyl group of the ligand and the main chain of Phe80 (Fig. 2). This contour may be a false property generated by CoMFA as there is a lack of diversity of compounds in this region, therefore no contours should be present there.Fig. 4


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)

CoMFA steric and electrostatic contour fields. Fields drawn with 85/15 proportion of favorable and unfavorable interactions. The most active compound (1) is shown
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: CoMFA steric and electrostatic contour fields. Fields drawn with 85/15 proportion of favorable and unfavorable interactions. The most active compound (1) is shown
Mentions: Figure 4 shows the steric and electrostatic contour maps generated via CoMFA modeling. Steric contour maps give information about the spatial volume of substituted groups at different positions. There were three green and one yellow contour regions located in the active site, with green meaning bulky groups are favored and yellow meaning bulky groups are disfavored. The yellow contour map may explain the lower activity of compounds 27, 28, 31, 33, 36 and 40, which have a bulky substituent in this position. Interestingly, there is a red contour region near the carbonyl group, meaning that less negative charge would be favored here. This is probably not connected with the sp2 hybridized oxygen atom but with the polarizability of the whole area. Importantly, the carbonyl group is a key moiety interacting with the active site of ABHD6 as the most important inhibitor contact is a hydrogen bond between the carbonyl group of the ligand and the main chain of Phe80 (Fig. 2). This contour may be a false property generated by CoMFA as there is a lack of diversity of compounds in this region, therefore no contours should be present there.Fig. 4

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.