Computational Biology and Chemistry Research Group, Vicerrectorado de Investigación, Universidad Catolica de Santa Maria de Arequipa, Arequipa, Peru.
Sustainable Innovative Biomaterials Department, Le Qara Research Center, Arequipa, Peru.
F1000Res. 2023 Jul 13;12:93. doi: 10.12688/f1000research.129943.2. eCollection 2023.
Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics-generalized Born surface area (MM-GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the arginase enzyme. The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. This work suggests the potential anti-leishmanial activity of the compounds and thus can be further and experimentally validated.
利什曼病是一种死亡率很高的疾病，每年约有 150 万例新发病例。尽管有新的方法和进展来对抗这种疾病，但仍没有有效的治疗方法。因此，本研究旨在筛选天然产物的结构类似物作为治疗利什曼病的新药候选物。我们应用了计算机辅助药物设计（CADD）方法，如虚拟筛选、分子对接、分子动力学模拟、分子力学-广义 Born 表面积（MM-GBSA）结合自由能估算和自由能扰动（FEP），旨在从具有抗利什曼病和抗精氨酸酶活性并能选择性结合精氨酸酶的天然产物中选择结构类似物。化合物 2H-1-苯并吡喃、3,4-二氢-2-(2-甲基苯基)-(9CI)、echioidinin 和矢车菊素对来自三种寄生虫的精氨酸酶靶标表现出良好的效果，且对潜在毒性呈阴性结果。echioidinin 和矢车菊素配体通过 MM-GBSA 和 FEP 方法在 pH 2.0 条件下在活性中心产生相互作用。这项工作表明了这些化合物具有潜在的抗利什曼病活性，因此可以进一步和实验验证。
