Malaria is a life-threatening infectious disease with an estimated 229 million cases in the year 2019 worldwide. Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (PfDXR) is one of the key enzymes in the biosynthetic pathway of isoprenoid, (required for parasite growth and survival) and considered as an attractive target for designing anti-malarial drugs. Fosmidomycin is an effective DXR inhibitor and has been proven effective and safe against P. falciparum in clinical trials. However, due to low bioavailability and inappropriate drug attributes, it is not a preferred option. The present study was performed to identify PfDXR inhibitors with improved pharmacology/safety. For this purpose, an integrated computational framework, comprising of pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulation and MM/PBSA, was used. The binding free energy analysis was performed using a focused library of phytochemicals established from medicinal plants. The study identified four bioactive compounds namely, Myricetin 3-rhamnoside, 7-O-Galloyltricetiflavan, (25S)-5-beta-spirostan-3-beta-ol 3-O-beta-d-glucopyranosyl-(1->2)-beta-d-glucopyranoside, and Oleanolic acid 28-O-beta-d-glucopyranoside as potential inhibitors of PfDXR. The selection of these four compounds was based on pharmacophore mapping, docking score, binding stability, molecular interactions with the residues of PfDXR active site, binding stability and free energy estimation. In conclusion, medicinal plant-based scaffolds were predicted with enhanced efficacy and adequate physiochemical/pharmacokinetic profile that might be helpful in controlling malaria.

疟疾是威胁生命的传染病，2019年全球估计有2.29亿病例。恶性疟原虫1-脱氧d -xylulose -5-磷酸还原（PfDXR）是，（用于寄生虫生长和存活），并认为是一种有吸引力的靶标用于设计抗疟疾药物中的类异戊二烯的生物合成途径的关键酶之一。Fosmidomycin是有效的DXR抑制剂，已被证明对恶性疟原虫有效且安全。在临床试验中。但是，由于生物利用度低和药物属性不当，因此不是首选方法。进行本研究以鉴定具有改善的药理学/安全性的PfDXR抑制剂。为此，使用了包括药效团模型，虚拟筛选，分子对接，分子动力学（MD）模拟和MM / PBSA在内的集成计算框架。使用从药用植物建立的聚焦植物化学文库进行结合自由能分析。该研究确定了四种生物活性化合物，即杨梅素3-鼠李糖苷，7-O-加洛氨甘油三黄酮，（25S）-5-β-螺旋素-3-β-ol3-O-β- d-吡喃葡萄糖基- （1-> 2） -beta- d-吡喃葡萄糖苷和齐墩果酸28-O-beta- d-吡喃葡萄糖苷作为PfDXR的潜在抑制剂。这四种化合物的选择基于药效基团定位，对接得分，结合稳定性，与PfDXR活性位点残基的分子相互作用，结合稳定性和自由能估计。总之，预计基于药用植物的支架具有增强的功效和足够的理化/药代动力学特征，可能有助于控制疟疾。