Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D QSAR approaches

Abstract

Schizophrenia is a complex disorder of thinking and behaviour (0.3−0.7% of the population is affected). The over-expression of phosphodiesterase 10A (PDE10A) enzyme may be a potential target for schizophrenia and Huntington’s disease. Because 3D QSAR analysis is one of the most frequently used modelling techniques, in the present study, five different 3D QSAR tools, namely CoMFA, CoMSIA, kNN-MFA, Open3DQSAR and topomer CoMFA methods, were used on a dataset of pyrimidine-based PDE10A inhibitors. All developed models were validated internally and externally. The non-commercial Open3DQSAR produced the best statistical results amongst 3D QSAR tools. The structural interpretations obtained from different methods were thoroughly analysed and were justified on the basis of information obtained from the crystal structure. Information from one method was mostly validated by the results of other methods and vice versa. In the current work, the use of multiple tools in the same analysis revealed more complete information about the structural requirements of these compounds. On the basis of the observations of the 3D QSAR studies, 12 new compounds were designed for better PDE10A inhibitory activity. The current investigation may help in further designing new PDE10A inhibitors with promising activity.

Keywords:

• Schizophrenia
• phosphodiesterase 10A
• k-nearest neighbour molecular field analysis
• CoMFA
• Topomer CoMFA
• Open3DQSAR

Acknowledgements

S. Gayen would like to thank the University Grants Commission (UGC), New Delhi for awarding UGC-Start up grant (No. F.30-106/2015-BSR). We also thank the support from Jadavpur University, Kolkata, India and Dr. Harisingh Gour University, Sagar, India.