Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi 630 003, Tamil Nadu, India.
Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu 600 031, India.
Comput Biol Chem. 2023 Dec;107:107942. doi: 10.1016/j.compbiolchem.2023.107942. Epub 2023 Aug 23.
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.
结核病（TB）是由结核分枝杆菌（MTB）引起的，仍然是全球健康的主要威胁，多药和广泛耐药菌株的出现构成了严重挑战。因此，了解 MTB 毒力和疾病发病机制的分子基础对于开发有效的治疗策略至关重要。靶向参与中心代谢的蛋白质已被认为是对抗 MTB 的一种有前途的治疗方法。在这方面，来自乙酰磷酸产生乙酸盐的乙酸代谢途径的酶 AckA 是各种致病生物的重要药物靶标。因此，本研究旨在通过计算机方法识别潜在的 AckA 抑制剂，包括分子建模、分子动力学模拟（MDS）和高通量虚拟筛选（HTVS）以及随后的 ADMETox、MMGBSA、密度泛函理论（DFT）计算。对 ZINC 数据库中的 100 万个化合物进行 HTVS 针对 AckA 的结果是前五个命中（ZINC82048449、ZINC1219737510、ZINC1771921358、ZINC119699567 和 ZINC1427100376），具有更好的结合亲和力和最佳结合自由能。复合物上的 MDS 研究表明，关键残基 Asn195、Asp266、Phe267、Gly314 和 Asn318 在顶级化合物与 AckA 的稳定相互作用中发挥了重要作用。这些结果深入了解了先导物与 AckA 最佳结合的情况，有助于合理设计新型治疗剂。因此，鉴定出的先导化合物可能是针对 AckA 的有前途的化合物，并可能成为治疗结核病的潜在治疗方式。我们的研究结果为抑制乙酸盐途径提供了有价值的见解，同时也为合理药物设计提供了蓝图。鉴定出的先导化合物有望成为针对 AckA 的有效化合物，从而为治疗结核病提供潜在的治疗途径。因此，我们的研究通过阐明 AckA 抑制剂，为有前途的结核病治疗方法提供了线索。通过利用计算机方法，揭示了具有阻止 MTB 乙酸盐途径中 AckA 作用潜力的有效化合物。这一突破为寻找新的有效的结核病治疗方法带来了希望，为解决这一全球健康挑战注入了新的活力。
