Department of Biochemistry, Bioinformatics and Molecular Biology Unit, Federal University of Technology Akure, Ondo State, Nigeria.
Department of Biochemistry, Adekunle Ajasin University, Akungba Akoko, Ondo State, Nigeria.
Curr Drug Discov Technol. 2021;18(4):554-569. doi: 10.2174/1570163817999200729122753.
In a bid to come up with effective compounds as inhibitors for antimalarial treatment, we built a library of 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Database@Taiwan.
The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolatereductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to offer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition.
We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking scores with both the wild type and mutant pfDHFR. They were further subjected to Induce Fit Docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the compounds were also considered. The inhibition profile of the compounds revealed that a number of compounds formed intermolecular interactions with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Most of the compounds can be considered as drug candidates due to their antiprotozoal activities and accordance with the Lipinski's Rule of Five (ROF).
The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.
为了开发有效的抗疟治疗抑制剂化合物，我们从台湾中药数据库中构建了一个包含 2000 种中药衍生化合物的库。
利用计算工具探索了野生型和突变型恶性疟原虫二氢叶酸还原酶（pfDHFR）的活性部位。pfDHFR 是预防雌性疟蚊感染疟疾的主要药物靶点之一，由于一些关键氨基酸残基的突变，它对药物（抗叶酸）继续产生耐药性。
我们利用虚拟高通量筛选和 glide XP 对接筛选化合物，发现 8 种化合物与野生型和突变型 pfDHFR 都具有有希望的对接评分。然后进一步进行诱导拟合对接（IFD）以确认它们的抑制能力。还考虑了化合物的 ADME 性质和生物活性谱。化合物的抑制谱表明，许多化合物与 ASP54、ILE14、LEU164、SER108/ASN108、ARG122 和 ASP58 形成了分子间相互作用。由于这些化合物具有抗原生动物活性并且符合 Lipinski 的五规则（ROF），因此大多数化合物可以被认为是候选药物。
本研究的结果应进一步研究，以证明这些化合物作为比抗叶酸更好的药物候选物的疗效。
