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
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.