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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.


a,b Root mean square deviations (RMSD) during molecular dynamics (MD) simulations. a Inhibitor 6 RMSD compared to initial position. b Complex RMSD compared to initial position
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Fig6: a,b Root mean square deviations (RMSD) during molecular dynamics (MD) simulations. a Inhibitor 6 RMSD compared to initial position. b Complex RMSD compared to initial position

Mentions: The investigated compounds are irreversible inhibitors of ABHD6. In order to study the first events of inhibitor binding, before formation of a covalent bond between the ligand carbonyl group and a side chain of Ser148 [17, 25]. MD simulations were performed for the complex of compound 6 with ABHD6. The complex was stable during simulations, as demonstrated by the decreasing value of potential energy for the complex (Fig. 5) and the complex RMSD (Fig. 6b). The position of 6 in the binding site of ABHD6 was relatively stable, as indicated by the ligand RMSD value below 3 Å (Fig. 6a). Figure 7 shows protein backbone RMSF during simulation. The greatest RMSF value (over 4 Å) has been found for helix end Gly193-Ser194 and Val224. During simulations it was observed that the distance between ligand carbonyl group and the main chain of Phe80 is increasing, weakening the respective hydrogen bond (Fig. 8). In contrast, a bond between the ligand carbonyl group and Ser148 is formed and maintained during the simulation. Although the distance is slightly increasing, there is a possibility to form a covalent bond necessary for irreversible inhibition (Fig. 8).Fig. 5


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)

a,b Root mean square deviations (RMSD) during molecular dynamics (MD) simulations. a Inhibitor 6 RMSD compared to initial position. b Complex RMSD compared to initial position
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: a,b Root mean square deviations (RMSD) during molecular dynamics (MD) simulations. a Inhibitor 6 RMSD compared to initial position. b Complex RMSD compared to initial position
Mentions: The investigated compounds are irreversible inhibitors of ABHD6. In order to study the first events of inhibitor binding, before formation of a covalent bond between the ligand carbonyl group and a side chain of Ser148 [17, 25]. MD simulations were performed for the complex of compound 6 with ABHD6. The complex was stable during simulations, as demonstrated by the decreasing value of potential energy for the complex (Fig. 5) and the complex RMSD (Fig. 6b). The position of 6 in the binding site of ABHD6 was relatively stable, as indicated by the ligand RMSD value below 3 Å (Fig. 6a). Figure 7 shows protein backbone RMSF during simulation. The greatest RMSF value (over 4 Å) has been found for helix end Gly193-Ser194 and Val224. During simulations it was observed that the distance between ligand carbonyl group and the main chain of Phe80 is increasing, weakening the respective hydrogen bond (Fig. 8). In contrast, a bond between the ligand carbonyl group and Ser148 is formed and maintained during the simulation. Although the distance is slightly increasing, there is a possibility to form a covalent bond necessary for irreversible inhibition (Fig. 8).Fig. 5

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.