An insight from computational approach to explore novel, high-affinity phosphodiesterase 10A inhibitors for neurological disorders

Abstract

The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington’s disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of −240.642 kJ/mol and −201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of −202.030 kJ/mol and −138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A.

Communicated by Ramaswamy H. Sarma

Keywords:

• PDE10A
• papaverine
• molecular docking
• steered molecular dynamics simulations
• umbrella sampling simulations

Acknowledgment

We gratefully acknowledge to the Director, CSIR-Institute of Himalayan Bioresource Technology, Palampur for providing the facilities to carry out this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Consent for publication

All the authors have read and approved the manuscript in all respects for publication.

Authors contribution

RP conceived of and designed the study. RP and BS analyzed and interpreted the data. DB and GZ Provided the chemical structures for computational studies and helped in improving the English language and finalizing the revised draft. All the authors critically revised it for important intellectual content.

Additional information

Funding

The CSIR support in the form of projects MLP:0201 for bioinformatics studies is highly acknowledged. G.V.Z. acknowledge the Ministry of Science and Higher Education of the Russian Federation within the framework of the grant agreement as government subsidies from the Federal budget in accordance with paragraph 4 of article 78.1 of the Budget Code of the Russian Federation (Moscow, 1 October 2020, No. 075-15-2020-777). BS acknowledges the Department of Biotechnology, New Delhi, India for providing junior research fellowship File No: DBTHRDPMU/JRF/BET-20/I/2020/AL/36. This manuscript represents CSIR-IHBT communication no. 5171.