Article: Screening for novel lead compounds targeting benzodiazepine allosteric binding site of wild-type and H129Y variant of GABAA receptor: an in-silico molecular docking study Journal: International Journal of Computational Biology and Drug Design (IJCBDD) 2021 Vol.14 No.5 pp.377 - 409 Abstract: Classical benzodiazepines (BZDs) bind at the high-affinity BZD binding site of the GABAA 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, GABAA 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 GABAA receptor. In addition, we have also identified compounds showing high affinity towards the H129Y GABAA 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 GABAA receptor variants. Inderscience Publishers - linking academia, business and industry through research

Title: 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

Authors: Sai Manohar Thota; Naresh Krishna Narasimha

Addresses: Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Puttaparthi – 515134, Andhra Pradesh, India ' Protein Structure and Function Laboratory, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Puttaparthi – 515134, Andhra Pradesh, India

Abstract: 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.

Keywords: GABA_A receptors; benzodiazepines; allosteric binding site; mutation; free energy; vibrational entropy; in silico docking; flavonoids; natural compounds; ADMET.

DOI: 10.1504/IJCBDD.2021.120131

International Journal of Computational Biology and Drug Design, 2021 Vol.14 No.5, pp.377 - 409

Received: 10 May 2021
Accepted: 05 Aug 2021
Published online: 07 Jan 2022 *

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

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Title: 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