In depth molecular interaction analyses of the complex of a proposed CTXM-inhibitor bound to the bacterial enzyme

A 'Thumb Rule for Antibiotic Design' against bacteria can be given as, 'The minimum pace of drug design ought to match the swiftness with which bacteria display cutting-edge resistance mechanisms; thereby outwitting the antibiotics and, in turn, the researchers'. Occurrence of drug resistance attributable to CXTM-variants in bacterial pathogens is widespread. In line with our above proposed thumb rule, the present article employed concatenation of virtual screening, docking and simulation to identify a potent in silico validated anti-CTXM-14 ligand. Specifically, this research used the 'MCULE' drug discovery platform to screen a total of 5 million candidate inhibitors to evaluate their binding efficacy with an antibiotic resistance enzyme, CTXM-14 found in bacterial pathogens. A new median approach between 'structure' and 'ligand'-based protocols was employed. Pharmacokinetic profiling was achieved by 'SWISS ADME'. Safety profile for humans was appraised by 'Toxicity Checker'. The complex consisting of the 'Top ligand' (obtained from the screen) harbored within the active pocket of the bacterial CTXM-14 was subjected to 60 ns molecular dynamics simulation with the aid of licensed YASARA STRUCTURE v.21.8.27. Complex tasks were performed by YANACONDA. Fine resolution figures (notably, plots generated from trajectory analyses) were constructed. Simulation snaps were acquired at every 250 picoseconds of the run. The ligand having the IUPAC name as 1-Amino-3-(4-hydroxyphenyl)pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile demonstrated the overall best binding with CTXM-14. Fifteen amino acid residues were found to line the interacting pocket. Remarkably, all of these interacting residues were found to be present among the interacting residues displayed by the reference complex as well, i.e. CTXM-14:Vaborbactam complex (PDB ID 6V7H). A total of 240 simulation snaps were retrieved. The RMSD plot revealed that a plateau was achieved at 32 ns, after which the backbone RMSD fluctuations remained confined within 1.4-2 Å. Video recording of molecular actions was also achieved. In conclusion, this study provides a fresh lead molecule, 1-Amino-3-(4-hydroxyphenyl)pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile against bacterial CTXM-14 protein. The study utilized a new median approach between 'structure' and 'ligand'-based drug design. The lead molecule passed ADMET conditions and an array of medicinal chemistry filters, and is further supported by a stable molecular dynamics. An acceptable skin permeation supports its probable use in antibiotic creams. Moreover, the study provides a clear 'Thumb Rule for Antibiotic Design' against bacteria, which although often assumed, can be clearly stated for the first time. Synthesis of the screening-proposed molecule followed by in-vitro and in-vivo validation is highly recommended.Communicated by Ramaswamy H. Sarma.