Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Chem Biol Drug Des. 2012 Aug;80(2):300-14. doi: 10.1111/j.1747-0285.2012.01403.x. Epub 2012 Jun 11.
Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q(2) = 0.562 and r(2) = 0.995, comparative molecular similarity indices analysis: q(2) = 0.549 and r(2) = 0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features.
耐甲氧西林金黄色葡萄球菌已成为一个主要的健康问题，需要新的治疗药物。金黄色葡萄球菌天冬酰胺酶 A 酶有助于细菌与宿主细胞细胞壁的黏附；因此，小分子抑制金黄色葡萄球菌天冬酰胺酶 A 可以作为抗耐甲氧西林金黄色葡萄球菌的潜在抗菌药物。本研究集中于鉴定一系列类罗丹明、哒嗪酮和吡唑硫酮类似物作为金黄色葡萄球菌天冬酰胺酶 A 抑制剂的 3D 药效特征。使用遗传算法和数据库的超分子配准线性分配，使用代表分子构建药效模型。然后，将鉴定出的药效点用于创建三维定量构效关系的对齐假设。比较分子场分析和比较分子相似性指数分析实验的结果非常吻合（比较分子场分析：q(2) = 0.562，r(2) = 0.995，比较分子相似性指数分析：q(2) = 0.549，r(2) = 0.978），并且能够根据化合物的结构特征一致地解释生物活性的变化。结果也与药效特征的结果一致。
