Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India.
J Biomol Struct Dyn. 2024 Feb-Mar;42(4):2111-2126. doi: 10.1080/07391102.2023.2203254. Epub 2023 Apr 25.
Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (, and ) as less toxic potential modulators of Mtb EthR protein. Compounds , and were having the significant docking score of -12.696 Kcal/mol, -12.681 Kcal/mol and -15.293 Kcal/mol towards the protein with less MAO-A and B affinity [compound : MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound : MAO A (> -2.00 Kcal/mol) and MAO B (> -2.00 Kcal/mol) and compound : MAO A (> -5.678 Kcal/mol) and MAO B (> -6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid.Communicated by Ramaswamy H. Sarma.
利奈唑胺是过去 35 年来唯一获批的首个恶唑烷酮类抗菌药物。它对 具有抑菌作用，是 BPaL 方案（贝达喹啉、德拉马尼和利奈唑胺）的重要组成部分，该方案于 2019 年获得 FDA 批准，用于治疗广泛耐药性结核病或耐多药结核病。尽管利奈唑胺具有独特的作用机制，但它具有相当大的毒性风险，包括骨髓抑制和血清素综合征（SS），分别由抑制线粒体蛋白合成（MPS）和单胺氧化酶（MAO）引起。基于利奈唑胺的结构毒性关系（STR），在这项工作中，我们使用生物等排替代方法对利奈唑胺的 C 环和/或 C-5 位进行结构优化，以降低骨髓抑制和致血清毒性。广泛的分层多步对接、药物相似性预测、分子结合相互作用分析和毒性评估确定了三种有前途的化合物（、和 ）作为 Mtb EthR 蛋白的潜在低毒调节剂。化合物 、和 对 蛋白的结合能分别为-12.696 Kcal/mol、-12.681 Kcal/mol 和-15.293 Kcal/mol，且对 MAO-A 和 MAO-B 的亲和力较低[化合物 ：MAO A（-4.799 Kcal/mol）和 MAO B（-6.552 Kcal/mol）；化合物 ：MAO A（> -2.00 Kcal/mol）和 MAO B（> -2.00 Kcal/mol）和化合物 ：MAO A（> -5.678 Kcal/mol）和 MAO B（> -6.537 Kcal/mol）]，且它们均不会引起骨髓抑制的副作用（如白细胞减少症）。分子动力学模拟结果和结合自由能估算与对接分析吻合较好，表明所提出的化合物比利奈唑胺更有效地结合和抑制 EthR 蛋白。使用密度泛函理论（DFT）评估了量子力学和电学特性，结果也表明所提出的化合物比利奈唑胺更具反应性。
