QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

Abstract

Computational enzymology is a rapidly developing area that uniquely provides deep insight into the fundamental processes of biological catalysis at the atomic level. Such in‐depth insight can ultimately be employed in designing potential inhibitors against the targets of interest. Computational enzymology covers a wide range of in‐silico approaches for investigating the enzyme‐catalyzed reaction mechanisms, among which combined quantum mechanics (QM) /molecular mechanics (MM) approaches have gained a lot of attention nowadays. This advanced approach generally involves a QM method (i. e. a method that estimates the electronic structure of the active site) and a simpler MM method (a method that includes the enzyme environment) to understand the enzymatic reactions. The QM/MM method has been widely tested in understanding the molecular mechanisms both at the structural and energetic levels and observed to best correlate with experimental studies of the enzymatic mechanism. It proposes a new mechanism that ultimately opens a new route for designing new potent, efficacious enzyme inhibitors. This review mainly covers wide applications of the ONIOM (Our own N‐layer Integrated molecular Orbital Molecular mechanics) method for decoding the enzymatic catalysis mechanism or designing potential small molecule inhibitors as treatment therapeutics in terms of free energy profiles. Moreover, this article also highlights employing QM/MM method in comprehending the mechanisms for drug metabolism and resistance (owing to mutations). This write‐up may encourage medicinal chemists and molecular biologists to explore this approach to propose more promising therapeutics to improve the quality of treatment.

Computational Insights into Amide Bond Formation Catalyzed by the Condensation Domain of Nonribosomal Peptide Synthetases

“…It is noted that all ONIOM calculations were conducted within a mechanical embedding (ME) formalism. This methodology has previously been successfully used to investigate a range of enzymatic mechanisms. − The % occurrence of key hydrogen bonds was calculated using distance and the angle cutoffs between the key atomic centers. For instance, the distance between the X and Y centers in the X (−H)··· Y hydrogen bond was selected as 3.0 Å while concomitantly the X ···H··· Y angle was taken into account and had to lie in the range 140–180°.…”

Antimicrobial Nanocomposites from Chitosan and Squash Synthesized Nano‐Selenium Eradicate Skin Pathogens

“…This shift is attributed to the heightened demand for herbal remedies, their affordability, and a growing awareness of the potential adverse effects of modern pharmaceuticals. In recent years, healthcare professionals have observed a rise in patients with challenging‐to‐treat wounds and burns, emphasizing the importance of exploring alternative treatments [23] …”