Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation

Abstract

DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase that ensures the regulation of DNA topology and has been genetically demonstrated to be a bactericidal drug target. Availability of crystal structure of M. smegmatics GyrB in complex with one of the aminopyrazinamides facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. Further the model was validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel DNA gyrase B inhibitors. This study led to the identification of fifteen potential compounds with IC50 values in the range of 1.5-45.5 µM against M. smegmatics GyrB and 1.16-25 µM in MTB supercoiling assay. Lead 11 emerged as the most potential compound, exhibiting inhibition of MTB DNA gyrase supercoiling with an IC50 of 1.16±0.25 µM, and M. smegmatics GyrB IC50 of 1.5±0.12 µM and hence could be further developed as novel inhibitor for mycobacterial GyrB.

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

“…All this background has made the DNA topoisomerases a satisfying target for novel anti-TB drugs. The mycobacterial DNA topoisomerase II, namely DNA gyrase (GyrB), was the second most exploited enzyme, seen four times [44,45,46,47]. It was observed, with the aid of ligand and structure-based screening, that novel inhibitors could be seen to be targeting this enzyme.…”

“…We found 40 different PDBs used in the 46 evaluated manuscripts. The most applied PDB was 4B6C, which was seen four times (8%) [44,45,46,47]. 4B6C codes for the structure of M. smegmatis GyrB ATPase domain in complex with an aminopyrazinamide, a known inhibitor of the GyrB [71].…”

“…Also, Saxena et al [45] did a sequence alignment of the M. smegmatis and M. tuberculosis DNA GyrB and found that they share 87.4% similarity. This crystallized protein was used as a structural framework for structure-based virtual screening of databases [44,46], molecular docking studies [47], and structure‒activity relationship (SAR) assay [45].…”

“…Validation of the virtual screening procedures or in silico methodologies is not mandatory, but it is often seen. Despite this, of the 46 papers, only 19 did any kind of assay to validate their results [6,11,12,13,14,15,16,23,33,35,38,39,44,46,47,55,56,58,61]. Validation trials were considered if they performed a redocking experiment with the targeted protein and its original ligand, compared the binding conformations of the found molecules and the original ligands on the targeted protein, and performed a molecular dynamics simulation.…”

Structural Models for the Design of PKMzeta Inhibitors with Neurobiological Indications

“…Total of 22000 compounds were selected using HTVS screening, which were further subjected to Glide SP. Eventually top 1000 compounds were selected from the screened list Glide SP with a glide score may be less than or equal to −6 kcal/mol, along with one or more hydrogen bonds 38. These short‐listed compounds were then subjected to Glide XP, which gave the compounds with scores ranging from −7.43 to −10.10 kcal/mol.…”