Khurana Juhi, Shrivastava Ashish, Singh Ashutosh, Gupta Ashish
Epigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India.
Bioinformatics Lab, Department of Life Sciences, Shiv Nadar University, Greater Noida, India.
J Biomol Struct Dyn. 2023 Feb;41(2):736-752. doi: 10.1080/07391102.2021.2011418. Epub 2021 Dec 8.
Although malaria related cases and deaths have consistently declined over time, growing resistance to existing anti-malarial drugs in remains a matter of extreme concern. Since we rely so heavily on use of chemotherapy for malaria treatment and knowing that all the available anti-malarial drug will become virtually useless in the near future, we have to increase our understanding of basic biology of the parasite as well as characterize new molecular targets that can be exploited for anti-malarial therapy. In the present study, PfRUVBLs (AAA family member proteins) were evaluated for their potential as novel anti-malarial drug target candidates, using computational approaches. Virtual High-throughput screening of various pharmacophore libraries obtained from three different databases (which included, Asinex, ZINC15 & PubChem) followed by extra precision docking, resulted in identification of relevant hit compounds that showed binding affinity with the active region of PfRUVBL1 protein. Based on molecular docking data, MD simulations, and protein-ligand interaction studies, combined with toxicity assessment & ADME profiling data, at least three best hits were eventually identified that could be novel potent inhibitors of PfRUVBL1 protein and can be further tested for anti-malarial activity using protocols. Communicated by Ramaswamy H. Sarma.
尽管与疟疾相关的病例和死亡人数一直呈下降趋势，但疟原虫对现有抗疟药物的耐药性不断增强，这仍然是一个极为令人担忧的问题。由于我们在很大程度上依赖化疗来治疗疟疾，并且知道所有现有的抗疟药物在不久的将来几乎都会变得无用，因此我们必须加深对疟原虫基本生物学的理解，并确定可用于抗疟治疗的新分子靶点。在本研究中，使用计算方法评估了疟原虫RUVBLs（AAA家族成员蛋白）作为新型抗疟药物靶点候选物的潜力。对从三个不同数据库（包括Asinex、ZINC15和PubChem）获得的各种药效团库进行虚拟高通量筛选，然后进行高精度对接，从而鉴定出与PfRUVBL1蛋白活性区域具有结合亲和力的相关命中化合物。基于分子对接数据、分子动力学模拟和蛋白质-配体相互作用研究，结合毒性评估和药物代谢动力学（ADME）分析数据，最终确定了至少三种最佳命中化合物，它们可能是PfRUVBL1蛋白的新型强效抑制剂，并可使用相关方案进一步测试其抗疟活性。由拉马斯瓦米·H·萨尔马传达。
