Computational Drug Design and Docking Studies of Thiazole Derivatives Targeting Bacterial DNA Gyrase

Abstract

The emergent antimicrobial resistance (AMR) has required generating new antibacterial substances with distinct functions. DNA gyrase- particularly the subunit GyrB has been identified as a favorable bacterial target because it contains a highly conserved ATP binding site, and is required in supercoiling of DNA. Broad-spectrum pharmacological agents flaunted by thiazole derivatives have been proven to be highly antibacterial agents when rationally prepared to target gyrB. The review indicates the use of modern computational methods of drug design--QSAR modeling, molecular docking, molecular dynamics and ADMET prediction--to identify and optimize thiazole-based DNA gyrase inhibitors. Such in silico approaches enabled weeks worth of candidate screening in analogy of thiazole compounds with high binding affinities, good pharmacokinetics and low toxicity. Remarkably some of the lead substances showed good inhibition of bacteria in an in vivo setting with low bacterial load and gentle side effects on animal subjects. Not only that, the thiazole derivatives also demonstrated the capability of overcoming the existing resistance mechanisms like GyrA mutations and efflux pump by inhibiting a region less prone to mutations in GyrB. The combination of computer and experimental-based methods is not only advancing the process of drug discovery but also helping in enabling the design of resistance evading antibacterial agents with structural novelty. Therefore, thiazole-based inhibitors are an interesting opportunity in next-generation antibiotics with the constantly growing AMR problems around the globe.