Molecular docking based screening of GABA (A) receptor inhibitors from plant derivatives

The present antipsychotic drugs have known to show serious concerns like extra pyramidal side effects therefore, pursuit for novel antipsychotic GABAnergic drugs has lately focused on the folkloric medicine from plant derivatives as better treatment option of schizophrenia. The present study centers to identify potential inhibitors of plant origin for GABA receptor through in silico approaches. Three compound datasets were undertaken in the study. The first set consisted of seven compounds which included Magnolol, Honokiol and other plant derivatives. The second set consisted of 16 derivatives of N-diarylalkenyl-piperidinecarboxylic acid synthesized by Zheng et al., 2006. The third dataset had thirty two compounds which were Magnolol and Honokiol analogues synthesized by Fuchs et al., 2014. All the compounds were docked at the allosteric site of the GABA (A) receptor. The compounds were further tested for ADMET and biological activity. We observed Honokiol and its derivatives demonstrated superior druglike properties than any compound undertaken in the study. Further, compound 61 [2-(4-methoxyphenyl)-4-propylphenol] of dataset three - a synthetic derivative of honokiol had better profile than its parent compound. In a possible attempt to identify compound with even better efficacious compound than 61, virtual screening was performed, 135 compounds akin to compound 61 were retrieved. Interestingly none of the 135 compounds showed better druggable properties than compound 61. Our in silico pharmacological profiling of compounds is in coherence and is complemented by the findings of Fuchs et al, which also revealed compound 61 to be the good potentiator of GABA receptor. ABBREVIATIONS: GABA (A) R - Gamma Amino Butyric Acid Receptor, subtype A, GPCR - G Protein Coupled Receptor, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank, PLP - Piece wise Linear Potential, T.E.S.T - Toxicity Estimation Software Tool, TCM - Traditional Chinese Medicine.