Staphylococcus aureus is a lethal pathogen that can cause various bacterial infections. This study targets the CrtM enzyme of S. aureus, which is crucial for synthesizing golden carotenoid pigment: staphyloxanthin, which provides anti-oxidant activity to this bacterium for combating antimicrobial resistance inside the host cell. The present investigation quests for human SQS inhibitors against the CrtM enzyme by employing structure-based drug design approaches including induced fit docking (IFD), molecular dynamic (MD) simulations, and binding free energy calculations. Depending upon the docking scores, two compounds, lapaquistat acetate and squalestatin analog 20, were identified as the lead molecules exhibit higher affinity toward the CrtM enzyme. These docked complexes were further subjected to 100 ns MD simulation and several thermodynamics parameters were analyzed. Further, the binding free energies (ΔG) were calculated for each simulated protein–ligand complex to study the stability of molecular contacts using the MM-GBSA approach. Pre-ADMET analysis was conducted for systematic evaluation of physicochemical and medicinal chemistry properties of these compounds. The above study suggested that lapaquistat acetate and squalestatin analog 20 can be selected as potential lead candidates with promising binding affinity for the S. aureus CrtM enzyme. This study might provide insights into the discovery of potential drug candidates for S. aureus with a high therapeutic index.

金黄色葡萄球菌是一种致命的病原体，可引起各种细菌感染。本研究针对金黄色葡萄球菌的 CrtM 酶，该酶对于合成金色类胡萝卜素色素至关重要：葡萄球菌黄质，它为这种细菌提供抗氧化活性，以对抗宿主细胞内的抗菌素耐药性。目前的研究通过采用基于结构的药物设计方法寻找针对 CrtM 酶的人类 SQS 抑制剂，包括诱导拟合对接 （IFD）、分子动力学 （MD） 模拟和结合自由能计算根据对接分数，确定了两种化合物，即 lapaquistat acetate 和 squalestatin 类似物 20，因为先导分子对 CrtM 酶表现出更高的亲和力。这些对接的复合物进一步进行了 100 ns MD 模拟，并分析了几个热力学参数。此外，计算每个模拟蛋白质-配体复合物的结合自由能 （ΔG），以使用 MM-GBSA 方法研究分子接触的稳定性。进行 Pre-ADMET 分析以系统评价这些化合物的物理化学和药物化学性质。上述研究表明，lapaquistat acetate 和 squalestatin 类似物 20 可以选择作为潜在的主要候选物，对金黄色葡萄球菌 CrtM 酶具有很好的结合亲和力。这项研究可能为发现具有高治疗指数的金黄色葡萄球菌的潜在候选药物提供见解。