Computational attributes of protein kinase-C gamma C2-domain & virtual screening for small molecules: elucidation from meta-dynamics simulations & free-energy calculations

Abstract

Epilepsy, a moderate to chronic neuropathological condition, is induced by the acute blockage of synaptic and voltage-gated inhibitory conduction or through the activation of synaptic and voltage-gated excitatory conduction. The regulation of long-term potentiation (LTP) is important in the regulation of epileptic events, and its activity is linked to specific protein kinases. The PKC-γ subtype is a vaguely explored therapeutic target for neurological disorders, but in selected studies, it is proven to be a critical intermediate protein in LTP. This study utilized computational modelling approaches including receptor-based docking, QSAR followed by explicit binding score assessment method MM/GBSA, MM/PBSA (EDA) and MTD simulation-based FES iteration. This was performed to virtually screen the small molecule libraries, which comprised about 2.79 lacs compounds against the Ca²⁺-binding site of the PKC-γ-C2 regulatory domain. The screened molecules LIG-41 ([4-Oxo-4-(4-phenylmethoxyanilino) butyl] azanium) and LIG-16 (Emixustat) exhibit overall optimal attributes in the above-mentioned parameters. The two leads are expected to inhibit the Ca²⁺-mediated PKC-γ activity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Protein Kinase C gamma
• neurodegenerative diseases
• virtual-screening
• metadynamics
• free energy calculations

Acknowledgements

We acknowledge the University Grant Commission for providing a fellowship under scheme CSIR-UGC NET-JRF to Harvinder Singh (MAY-2018 315733). We would also like to acknowledge ICMR for providing Anupam Raja with an SRF fellowship under letter no. 45/30/2020/PHA/BMS. We thank Prajwal Nandekar, Kishore V. and Vinod Devaraji from Schrödinger, LLC for their insightful contribution regarding technical guidance.

Disclosure statement

The author declares no conflict of interest.

Additional information

Funding

This work was supported by Indian Council of Medical Research (ICMR), Govt. of India, University Grants Commission.