Exploring the therapeutic potential of Zonisamide derivatives through molecular docking and dynamic studies with GABARAP

Abstract

Computer based drug designing is an effective tool to shortlist promising drug molecules within short span of time.  Designing drugs for neurological disorders is a necessity as it has affected millions of lives. Zonisamide is an effective sulfonamide drug administered to control seizures in epilepsy. This work aims to identify promising Zonisamide derivatives that form more stable complexes with inhibitory neurotransmitter GABARAP. We have designed 32 Zonisamide derivatives. These derivatives were optimised using Gaussian 09 and they were docked to the target GABARAP using PyRx software. The hydrophobic groups substituted at the benzene have lowered the binding energy of Zonisamide in most of the cases. Such derivatives were examined for their drug properties, oral activity and safety using ProTox-II, OSIRIS Property Explorer, and LogBB_Pred servers. The GABARAP residues engaged in the interaction with the derivatives were noted from LigPlot⁺. The top three derivatives namely Z11 ((6-phenylbenzo[d]isoxazol-3-yl)methanesulfonamide), Z19 (5-(tert-butyl)benzo[d]isoxazol-3-yl) methanesulfonamide, and Z20 (5-phenylbenzo[d]isoxazol-3-yl)methanesulfonamide were finalised and the molecular dynamic simulation of their complexes were carried out using GROMACS 2020. Each of the finalised complexes was analysed for its stability, residue flexibility, compactness, solvent accessible surface area and energy. Among the three derivatives, we propose Z11 as the potential GABARAP modulator.