Quantitative Structure-Activity-Amino Acid Relationship of Benzodiazepines and Thienodiazepine via Molecular Docking Simulation.

INTRODUCTION

Benzodiazepine (BZD) and thienodiazepine (TND) congeners are highly effective in managing central nervous system (CNS) disorders such as anxiety, insomnia, depression, and epilepsy. However, this class of compounds should be revitalized through the development of new molecules with minimal side effects and reduced potential for dependence. The BZDs and TNDs can occupy the BZD receptor situated at the allosteric site of gamma-aminobutyric acid type A (GABAA) receptor and facilitate the GABAA-mediated chloride ion channel opening action.

METHODS

The present study aims to structure-based docking of 29 BZDs and TNDs with binding affinity to enhance the allosteric action on GABAA and to predict the biochemical mechanisms at the target. This aspect has been scarcely explored; therefore, our objective is to predict the key amino acids within the target that favor interactions with BZDs and TNDs using quantitative structure-activity-amino acid relationship (QSAAR) analysis.

RESULTS

The developed docking and QSAAR models can explain how interacting amino acids affect biological activity in terms of GABAA receptor binding affinity of BZDs and TNDs.

DISCUSSION: The QSAAR establishes a quantitative relationship between biological activity and critical amino acids interacting with various groups of chemical compounds.

CONCLUSION

The above QSAAR model identifies GLN1239, SER1240, THR1242, and VAL1247 as significant contributors to activity with an R-value of 0.77. Therefore, these interacting amino acids are responsible for the compounds' agonistic activity.