Dahmer Bruno Rampanelli, Ethur Eduardo Miranda, Timmers Luis Fernando Saraiva Macedo
University of Taquari Valley - Univates, Avenida Avelino Tallini, 171, CEP, 95914-014, Lajeado, RS, Brazil; Programa de Pós-Graduação em Biotecnologia - PPGBiotec, University of Taquari Valley - Univates, Avenida Avelino Tallini, 171, CEP, 95914-014, Lajeado, RS, Brazil.
University of Taquari Valley - Univates, Avenida Avelino Tallini, 171, CEP, 95914-014, Lajeado, RS, Brazil; Programa de Pós-Graduação em Biotecnologia - PPGBiotec, University of Taquari Valley - Univates, Avenida Avelino Tallini, 171, CEP, 95914-014, Lajeado, RS, Brazil; Programa de Pós-Graduação em Ciências Médicas - PPGCM, University of Taquari Valley - Univates, Avenida Avelino Tallini, 171, CEP, 95914-014, Lajeado, RS, Brazil.
J Mol Graph Model. 2023 Jun;121:108404. doi: 10.1016/j.jmgm.2023.108404. Epub 2023 Jan 11.
Tuberculosis (TB) is a highly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). EPSP Synthase (MtEPSPS), the enzyme responsible for the sixth step of the shikimate pathway, is a potential target for the development of new drugs for the treatment of TB, as it is essential in mycobacteria but absent in humans. In this work, we performed virtual screening using sets of molecules from two databases and three crystallographic structures of MtEPSPS. The initial hits obtained from molecular docking were filtered based on predicted binding affinity and interactions with binding site residues. Subsequently, molecular dynamics simulations were carried out to analyze the stability of protein-ligand complexes. We have found that MtEPSPS forms stable interactions with several candidates, including already approved pharmaceutical drugs such as Conivaptan and Ribavirin monophosphate. In particular, Conivaptan had the highest estimated binding affinity with the open conformation of the enzyme. The complex formed between MtEPSPS and Ribavirin monophosphate was also energetically stable as shown by RMSD, Rg and FEL analyses, and the ligand was stabilized by hydrogen bonds with important residues of the binding site. The findings reported in this work could serve as the basis of promising scaffolds for the discovery, design, and development of new anti-TB drugs.
结核病（TB）是由结核分枝杆菌（Mtb）病原体引起的一种高度传染性疾病。5-烯醇丙酮酰莽草酸-3-磷酸合酶（MtEPSPS）是莽草酸途径第六步反应的负责酶，是开发治疗结核病新药的潜在靶点，因为它在分枝杆菌中必不可少，但在人类中不存在。在这项工作中，我们使用来自两个数据库的分子集和MtEPSPS的三种晶体结构进行了虚拟筛选。基于预测的结合亲和力和与结合位点残基的相互作用，对从分子对接获得的初始命中物进行了筛选。随后，进行了分子动力学模拟以分析蛋白质-配体复合物的稳定性。我们发现MtEPSPS与几种候选物形成稳定的相互作用，包括已批准的药物如考尼伐坦和单磷酸利巴韦林。特别是，考尼伐坦与该酶的开放构象具有最高的估计结合亲和力。如均方根偏差（RMSD）、回旋半径（Rg）和自由能景观（FEL）分析所示，MtEPSPS与单磷酸利巴韦林形成的复合物在能量上也很稳定，并且配体通过与结合位点重要残基的氢键而稳定。这项工作中报道的发现可为发现、设计和开发新型抗结核药物提供有前景的支架基础。
