Multilayer precision-based screening of potential inhibitors targeting Mycobacterium tuberculosis acetate kinase using in silico approaches.

Autor: Subramaniyan S; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi 630 003, Tamil Nadu, India., Nagarajan H; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi 630 003, Tamil Nadu, India., Vetrivel U; Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu 600 031, India., Jeyaraman J; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi 630 003, Tamil Nadu, India. Electronic address: jjbioinformatics@gmail.com.
Jazyk: angličtina
Zdroj: Computational biology and chemistry [Comput Biol Chem] 2023 Dec; Vol. 107, pp. 107942. Date of Electronic Publication: 2023 Aug 23.
DOI: 10.1016/j.compbiolchem.2023.107942
Abstrakt: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major threat to global health, with the emergence of multi-drug and extensively drug-resistant strains posing a serious challenge. Thereby, understanding the molecular basis of MTB virulence and disease pathogenesis is critical for developing effective therapeutic strategies. Targeting proteins involved in central metabolism has been recognized as a promising therapeutic approach to combat MTB. In this regard, the enzyme AckA of the acetate metabolic pathway which produces acetate from acetyl phosphate, is an important drug target for various pathogenic organisms. Therefore, this study aimed to identify potential AckA inhibitors through in silico methods, including molecular modeling, molecular dynamics simulation (MDS), and high-throughput virtual screening (HTVS) followed by ADMETox, MMGBSA, Density Functional Theory (DFT) calculations. HTVS of one million compounds from the ZINC database against AckA resulted in the top five hits (ZINC82048449, ZINC1219737510, ZINC1771921358, ZINC119699567, and ZINC1427100376) with better binding affinity and optimal binding free energy. MDS studies on complexes revealed that key residues, Asn195, Asp266, Phe267, Gly314, and Asn318 played a significant role in stable interactions of the top-ranked compounds to AckA. These outcomes provide insights into the optimal binding of the leads to inhibit the acetate pathway and aid in the rational design of novel therapeutic agents. Thus, the identified leads may act as promising compounds for targeting AckA and may serve as a potential therapeutic modality for treating TB. Our findings offer valuable insights into the inhibition of the acetate pathway, while also serving as a blueprint for rational drug design. The identified leads hold promise as compelling compounds for targeting AckA, thereby offering a potential therapeutic avenue for tackling TB. Thus, our study uncovers a pathway toward promising TB therapeutics by elucidating AckA inhibitors. By leveraging in silico methodologies, potent compounds that hold the potential to thwart AckA's role in MTB's acetate pathway have been unveiled. This breakthrough fosters optimism in the quest for novel and effective TB treatments, addressing a global health challenge with renewed vigor.
Competing Interests: Declaration of Competing Interest The authors affirm that they have no known financial or interpersonal conflicts that would have appeared to have an impact on the research presented in this study.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: