Screening for novel lead compounds targeting benzodiazepine allosteric binding site of wild-type and H129Y variant of GABA A receptor: an in-silico molecular docking study

摘要

Classical benzodiazepines (BZDs) bind at the high-affinity BZD binding site of the GABA_(A)receptor and enhance the natural effect of GABA resulting in anxiolytic, anticonvulsant, muscle relaxation and sedative effects. However, BZDs have unwanted side effects due to drug interaction, abuse and dependence. In addition, GABA_(A)receptor variants exhibit poor affinity for BZDs and could lead to pharmaco-resistance. Using virtual screening and in silico molecular docking, we have identified novel compounds with a high affinity towards the BZD binding site of the GABA_(A)receptor. In addition, we have also identified compounds showing high affinity towards the H129Y GABA_(A)variant, which could act as novel personalised medicines. We have predicted physiochemical, pharmacokinetics and drug-likeness properties of the high-affinity compounds. Further in vitro and in vivo validation could identify novel lead compounds against the BZD allosteric binding site of wild-type and H129Y GABA_(A)receptor variants.