Singh Satyendra, Prajapati Vijay Kumar
Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan 305817 India.
3 Biotech. 2022 Sep;12(9):235. doi: 10.1007/s13205-022-03304-1. Epub 2022 Aug 20.
Visceral leishmaniasis (VL) is a neglected tropical disease that mainly affects the poor population of the Indian, African, and South American subcontinent. The increasing resistance to antimonial and miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an anti-leishmanial drug with excellent efficacy and safety profile. In this study, three sequential docking protocols (HTVS, SP, and XP) were performed to screen the secondary metabolites ( = 6519) from the actinomycetes source against five key proteins involved in the metabolic pathway of . Those proteins were adenine phosphoribosyltransferase (PDB ID: 1QB7), trypanothione reductase (PDB ID: 2JK6), N-myristoyl transferase (PDB ID: 2WUU), pteridine reductase (PDB ID: 2XOX), and MAP kinase (PDB ID: 4QNY). Although the binding energy of top ligands was predicted using the MM-GBSA module of the Schrödinger suite. SP and XP docking mode resulted in 55 multi-targeted ligands against . MM-GBSA analysis selected the top 18 ligands with good-binding affinity and the binding-free energy for four proteins, as mentioned earlier, when compared with the miltefosine, paromomycin, and a reference ligand selected for each target. Finally, molecular dynamics simulation, post-MD-binding-free energy (MM-PBSA), and principal component analysis (PCA) proposed three best ligands (Adenosine pentaphosphate, Atetra P, and GDP-4-keto-6-deoxymannose) qualifying the above screening parameters and confirmed as a potential drug candidate to fight against parasites.
内脏利什曼病（VL）是一种被忽视的热带疾病，主要影响印度、非洲和南美洲次大陆的贫困人口。对锑剂和米替福新的耐药性不断增加，以及两性霉素B的频繁毒性，促使人们迫切需要开发一种具有优异疗效和安全性的抗利什曼药物。在本研究中，进行了三种连续的对接方案（HTVS、SP和XP），以筛选来自放线菌来源的次生代谢产物（=6519种）对参与代谢途径的五种关键蛋白质的作用。这些蛋白质分别是腺嘌呤磷酸核糖转移酶（PDB ID：1QB7）、锥虫硫醇还原酶（PDB ID：2JK6）、N-肉豆蔻酰转移酶（PDB ID：2WUU）、蝶啶还原酶（PDB ID：2XOX）和丝裂原活化蛋白激酶（PDB ID：4QNY）。尽管使用薛定谔套件的MM-GBSA模块预测了顶级配体的结合能。SP和XP对接模式产生了55种针对的多靶点配体。MM-GBSA分析选择了与米替福新、巴龙霉素以及为每个靶点选择的参考配体相比，对四种蛋白质具有良好结合亲和力和结合自由能的前18种配体。最后，分子动力学模拟、MD后结合自由能（MM-PBSA）和主成分分析（PCA）提出了三种最佳配体（五磷酸腺苷、Atetra P和GDP-4-酮-6-脱氧甘露糖），符合上述筛选参数，并被确认为对抗寄生虫的潜在药物候选物。
