Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (Council of Scientific & Industrial Research) P.O. CIMAP, Kukrail Picnic Spot Road, Lucknow-226015, Uttar Pradesh, India.
J Biomol Struct Dyn. 2010 Oct;28(2):201-10. doi: 10.1080/07391102.2010.10507353.
Dehydrosqualene synthase of Staphylococcus aureus is involved in the synthesis of golden carotenoid pigment staphyloxanthin. This pigment of S. aureus provides the antioxidant property to this bacterium to survive inside the host cell. Dehydrosqualene synthase (CrtM) is having structural similarity with the human squalene synthase enzyme which is involved in the cholesterol synthesis pathway in humans (Liu et al., 2008). Cholesterol lowering drugs were found to have inhibitory effect on dehydrosqualene synthase enzyme of S. aureus. The present study attempts to focus on squalene synthase inhibitors, lapaquistat acetate and squalestatins reported as cholesterol lowering agents in vitro and in vivo but not studied in context to dehydrosqualene synthase of S. aureus. Mode of binding of lapaquistat acetate and squalestatin analogs on dehydrosqualene synthase (CrtM) enzyme of S. aureus was identified by performing docking analysis with Scigress Explorer Ultra 7.7 docking software. Based on the molecular docking analysis, it was found that the His18, Arg45, Asp48, Asp52, Tyr129, Gln165, Asn168 and Asp172 residues interacted with comparatively high frequency with the inhibitors studied. Comparative docking study with Discovery studio 2.0 also confirmed the involvement of these residues of dehydrosqualene synthase enzyme with the inhibitors studied. This further confirms the importance of these residues in the enzyme function. In silico ADMET analysis was done to predict the ADMET properties of the standard drugs and test compounds. This might provide insights to develop new drugs to target the virulence factor, dehydrosqualene synthase of S. aureus.
金黄色葡萄球菌的脱水鲨烯合酶参与了金黄色素的合成。这种金黄色葡萄球菌的色素为该细菌提供了抗氧化特性，使其能够在宿主细胞内存活。脱水鲨烯合酶（CrtM）与人类鲨烯合酶在结构上具有相似性，后者参与了人类胆固醇合成途径（Liu 等人，2008）。降胆固醇药物被发现对金黄色葡萄球菌的脱水鲨烯合酶具有抑制作用。本研究试图专注于鲨烯合酶抑制剂拉帕奎塔酸酯和 squalestatins，它们在体外和体内被报道为降胆固醇药物，但在金黄色葡萄球菌的脱水鲨烯合酶方面尚未进行研究。通过使用 Scigress Explorer Ultra 7.7 对接软件进行对接分析，确定了拉帕奎塔酸酯和 squalestatin 类似物在金黄色葡萄球菌脱水鲨烯合酶（CrtM）酶上的结合模式。基于分子对接分析，发现 His18、Arg45、Asp48、Asp52、Tyr129、Gln165、Asn168 和 Asp172 残基与抑制剂研究以较高的频率相互作用。Discovery studio 2.0 的比较对接研究也证实了这些脱水鲨烯合酶酶残基与研究抑制剂的参与。这进一步证实了这些残基在酶功能中的重要性。进行了计算机 ADMET 分析，以预测标准药物和测试化合物的 ADMET 特性。这可能为开发针对金黄色葡萄球菌的毒力因子脱水鲨烯合酶的新药提供思路。
