In Silico Design, Molecular Docking, Drug-likeness Analysis, Bioactivity Score Prediction and Evaluation Anesthetic Activity of Some Novel Ketamine Analogues as pLGICs Inhibitors

Abstract

This paper aims to study the simulation of molecular fusion of ketamine isomers, molecular docking simulation of S & R ketamine isomers and (22) compounds of its analogues, each of these compounds has two enantiomers (S & R), was performed to predict their binding energies and inhibition constants, targeting Pentameric Ligand-gated Ion Channels receptor (pLGICs) to evaluate the anesthetic activity. The X-ray crystallographic structure of the target protein pLGICs receptor was downloaded from Protein Data Bank (PDB) website, with the code (4f8h). Discovery Studio Visualizer software was used to prepare PDB format files of designed molecules. The molecular docking interactions between the A chain of target protein and the ligands were performed using AutoDockTools v.1.5.6 software. The results indicated that (12) of the (S)- isomers of the designed molecules, (3, 4, 5, 7, 8, 9, 12, 18, 19, 20, 21 and 22) and (4) of the (R)-isomers (12, 20, 21 and 22) had lower binding energies than the standard ligands (S)-ketamine (JC9) and (R)-ketamine (RKE) and are predicted to have high affinities for pLGICs receptor. Furthermore, the drug-likeness results using the online Swiss ADME server showed that all of the designed molecules had good bioavailability, 0.55 and obeyed the Rule of five (RO5), with 0 violation. Bioactivity score results using Molinspiration web. server showed that all molecules had good ion channel modulator activities with bioactivity scores from 0.02 to 0.86, except molecules 11S and 11R, which are moderately active with bioactivity score -0.04. It is concluded that these compounds mediate their anesthetic activities by regulating the ion channels in central nervous system and lower doses of these compounds are required to mediate their anesthetic activities.