scholarly journals Computational Evaluation of Selectivity of Inhibition of Muscarinic Receptors M1-M4

2018 ◽  
Vol 1 (3) ◽  
pp. e00072 ◽  
Author(s):  
A.V. Mikurova ◽  
V.S. Skvortsov ◽  
O.A. Raevsky
Keyword(s):  
Molecular Dynamics ◽  
Muscarinic Receptors ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Regression Equations ◽  
Energy Characteristics ◽  
Independent Variables ◽  
Computational Evaluation ◽  
Average Accuracy ◽  
M3 Receptor

A set of models for preliminary estimation of the inhibition constant values of potential ligands for the 4 acetylcholine muscarinic receptors M1-M4 was developed. The study uses an information about three-dimensional structure of human M1, M2 and M4 receptors, as well as the M3 receptor model, constructed by homology based on the structure of the rat M3 receptor. The Ki values for 42 compounds were obtained from the sources. Modeling of “protein-ligand” complexes was performed using molecular docking and molecular dynamics procedures. The component energy characteristics of the complexes were calculated from data obtained from simulation of molecular dynamics by the MM-PBSA/MM-GBSA methods. These characteristics were used as independent variables to construct the linear regression equations for pKi value predicting. The equations obtained for each receptors allow us to predict pKi with an average accuracy of 0.65 logarithmic units.

scholarly journals Generalized predictive model of estimation of inhibition of muscarinic receptors M1-M5

2020 ◽  
Vol 3 (3) ◽  
pp. e00129
Author(s):  
A.V. Mikurova ◽  
V.S. Skvortsov ◽  
V.V. Grigoryev
Keyword(s):  
Predictive Model ◽  
Muscarinic Receptors ◽  
Three Dimensional ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Regression Equations ◽  
Energy Characteristics ◽  
Value Prediction ◽  
M3 Receptor ◽  
The Mean

A general predictive model for assessing the inhibition constant (K<sub>i</sub>) value of human acetylcholine muscarinic receptors M1-M5 by potential ligands has been constructed. We used information on the three-dimensional structure of human M1, M2, M4, and M5 receptors, as well as a model of the M3 receptor constructed according to homology based on the structure of the rat M3 receptor. A set of complexes of known inhibitors with the target receptor constructed by means of molecular docking, was selected using an additional option: the coincidence of the spatial position of 4 pharmacophore points of a tested inhibitor and tiotropium, for which the position in the crystal structure was known. For five types of M receptors 199 complexes with known K<sub>i</sub> values were selected. Based on the data obtained during molecular dynamics simulation of these complexes by means of the MM-PBSA/MM-GBSA methods, their energy characteristics were calculated. They were used as independent variables in linear regression equations for pK<sub>i</sub> value prediction. The R<sup>2</sup> prediction for the generalized equation was 0.7, and the mean prediction error was 0.55 logarithmic units with a range for pK<sub>i</sub>=4.7.

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