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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.


Experimental versus predicted pIC50 values for the training and test sets
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Related In: Results  -  Collection


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Fig3: Experimental versus predicted pIC50 values for the training and test sets

Mentions: The 3D-QSAR CoMFA model was built using Sybyl-X v. 2.1. The CoMFA model gave a cross-validated coefficient Q2 of 0.55 with an optimal component of 4, R2 of 0.98 and an F value of 346.762. The field contributions of parameters were 65.3 % and 34.7 % for the steric field and the electrostatic field descriptor, respectively. These statistical parameters indicate that the CoMFA model is statistically significant. Experimental and predicted IC50 values are presented in Table 1. It can be seen that they do not deviate significantly from each other (generally not more than 1 logarithmic unit). Figure 3 shows a very good correlation between the experimental and computed IC50 values for the training set, but a worse correlation for the test set. Most compounds from the training set were over-predicted. However, the value of the cross-validated coefficient Q2 (above 0.5) indicates the good internal predictability of the model.Fig. 3


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)

Experimental versus predicted pIC50 values for the training and test sets
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Experimental versus predicted pIC50 values for the training and test sets
Mentions: The 3D-QSAR CoMFA model was built using Sybyl-X v. 2.1. The CoMFA model gave a cross-validated coefficient Q2 of 0.55 with an optimal component of 4, R2 of 0.98 and an F value of 346.762. The field contributions of parameters were 65.3 % and 34.7 % for the steric field and the electrostatic field descriptor, respectively. These statistical parameters indicate that the CoMFA model is statistically significant. Experimental and predicted IC50 values are presented in Table 1. It can be seen that they do not deviate significantly from each other (generally not more than 1 logarithmic unit). Figure 3 shows a very good correlation between the experimental and computed IC50 values for the training set, but a worse correlation for the test set. Most compounds from the training set were over-predicted. However, the value of the cross-validated coefficient Q2 (above 0.5) indicates the good internal predictability of the model.Fig. 3

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.