Mehta Abijeet Singh, Snigdha Kirti, Potukuchi M Sharada, Tsonis Panagiotis A
Department of Biology, University of Dayton, Dayton, OH, USA.
School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
Hum Genomics. 2015 Apr 19;9(1):5. doi: 10.1186/s40246-015-0027-1.
Serogroup A of Neisseria meningitidis is the organism responsible for causing epidemic diseases in developing countries by a pilus-mediated adhesion to human brain endothelial cells. Type IV pilus assembly protein (PilF) associated with bacterial adhesion, aggregation, invasion, host cell signaling, surface motility, and natural transformation can be considered as a candidate for effective anti-meningococcal drug development. Since the crystal structure of PilF was not available, in the present study, it was modeled after the Z2491 strain (CAM09255.1) using crystal structure of chain A of Vibrio cholerae putative Ntpase EpsE (Protein Data Bank (PDB) ID: 1P9R) and then we based this analysis on sequence comparisons and structural similarity using in silico methods and docking processes, to design a suitable inhibitor molecule. The ligand 3-{(4S)-5-{[(1R)-1-cyclohexylethyl]amino}-4-[(5S)-5-(prop-2-en-1-yl) cyclopent-1-en-1-yl]-1,4-dihydro-7H-pyrrolo[2,3-d] pyrimidin-7-yl}-1,2-dideoxy-b-L-erythro-hex-1-en-3-ulofuranosyl binds to the protein with a binding energy of -8.10 kcal and showed a drug likeness of 0.952 with no predicted health hazard. It can be utilized as a potent inhibitor of N. meningitidis pilus-mediated adhesion to human brain endothelial cells preventing meningeal colonization.
脑膜炎奈瑟菌A血清群是通过菌毛介导黏附于人脑内皮细胞而在发展中国家引起流行性疾病的病原体。与细菌黏附、聚集、侵袭、宿主细胞信号传导、表面运动性及自然转化相关的IV型菌毛组装蛋白（PilF）可被视为有效的抗脑膜炎球菌药物研发的候选靶点。由于PilF的晶体结构尚未获得，在本研究中，利用霍乱弧菌假定的Ntpase EpsE的A链晶体结构（蛋白质数据库（PDB）ID：1P9R）对Z2491菌株（CAM09255.1）进行建模，然后基于序列比对和结构相似性，采用计算机模拟方法和对接过程来设计合适的抑制剂分子。配体3 - {（4S）-5 - {[（1R）-1 - 环己基乙基]氨基}-4 - [（5S）-5 - （丙-2 - 烯-1 - 基）环戊-1 - 烯-1 - 基]-1,4 - 二氢-7H - 吡咯并[2,3 - d]嘧啶-7 - 基}-1,2 - 二脱氧-β - L - 赤藓糖己-1 - 烯-3 - 呋喃糖基以-8.10千卡的结合能与该蛋白结合，药物相似性为0.952，且无预测的健康危害。它可作为脑膜炎奈瑟菌菌毛介导黏附于人脑内皮细胞的有效抑制剂，预防脑膜定植。
