Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Chem Biol Drug Des. 2013 Oct;82(4):418-28. doi: 10.1111/cbdd.12167.
Staphylococcus aureus is the leading cause of hospital-acquired infections in the United States. The emergence of multidrug-resistant strains of S. aureus has created an urgent need for new antibiotics. Staphylococcus aureus uses the sortase A enzyme to display surface virulence factors suggesting that compounds that inhibit its activity will function as potent anti-infective agents. Here, we report the identification of several inhibitors of sortase A using virtual screening methods that employ the relaxed complex scheme, an advanced computer-docking methodology that accounts for protein receptor flexibility. Experimental testing validates that several compounds identified in the screen inhibit the activity of sortase A. A lead compound based on the 2-phenyl-2,3-dihydro-1H-perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure-activity relationship studies.
金黄色葡萄球菌是美国医院获得性感染的主要原因。耐多药金黄色葡萄球菌菌株的出现，迫切需要新的抗生素。金黄色葡萄球菌使用 sortase A 酶来展示表面毒力因子，这表明抑制其活性的化合物将作为有效的抗感染药物。在这里，我们报告了使用虚拟筛选方法鉴定出几种 sortase A 的抑制剂，该方法采用了松弛复合物方案，这是一种先进的计算机对接方法，可考虑蛋白质受体的灵活性。实验测试证实，筛选出的几种化合物可抑制 sortase A 的活性。以 2-苯基-2,3-二氢-1H-嘧啶为骨架的一种先导化合物特别有前景，并用分子动力学模拟和初步的构效关系研究进一步研究了其结合机制。
