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Comparative molecular field analysis and hologram quantitative structure activity relationship studies of pyrimidine series as potent phosphodiesterase 10A inhibitors
Author(s) -
Gholami Rostami Elham,
Fatemi Mohammad H.
Publication year - 2018
Publication title -
journal of the chinese chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.329
H-Index - 45
eISSN - 2192-6549
pISSN - 0009-4536
DOI - 10.1002/jccs.201700435
Subject(s) - chemistry , quantitative structure–activity relationship , steric effects , pyrimidine , stereochemistry , substituent , loo , phosphodiesterase , computational chemistry , enzyme , organic chemistry
The inhibition of phosphodiesterase (PDE) 10A enzyme as an alternative approach is shown to have potential in the current treatment of schizophrenia. In the present work, the inhibition activity of 87 structurally diverse pyrimidine derivatives as PDE10A inhibitors were subjected to 2‐dimensional quantitative structure activity relationship (2D‐QSAR) and 3D‐QSAR studies using hologram QSAR and comparative molecular field analysis (CoMFA), respectively. The best CoMFA model gave a noncross‐validated correlation coefficient, ( r ncv 2 ) = 0.977, SE train = 0.247 and predictive correlation coefficient ( r pred 2 ) = 0.957, and SE test = 0.358. For the hologram QSAR (HQSAR) model, the similar parameters were r ncv 2 = 0.889 , SE train = 0.565, r pred 2 = 0.801 , and SE test = 0.872. The leave‐one‐out (LOO) cross‐validated r 2 ( q 2 ) were 0.78 and 0.8 for the CoMFA and HQSAR models, respectively. These statistics indicate that the CoMFA model is more satisfactory than the HQSAR. Analysis of CoMFA steric and electrostatic contour maps strongly demonstrate that the presence of bulky group at the end of R 1 substituent, especially heterocyclic aromatic rings, increase the inhibitory activities, and electronegative groups, such as alkoxide at the R 2 position, enhance the inhibitory activities of studied chemicals. The results of this study serves as a guide for the possible modifications and designing of novel pyrimidine derivatives as new potent PDE10A inhibitors.