Haiwang Djefoulna Victorien Hermann, Atiya Atiya Maxime, Fifen Jean Jules, Conradie Jeanet
Quantum Theory and Applications Unit, Department of Physics, Faculty of Science, University of Ngaoundere, P.O. Box 454, Ngaoundere, Cameroon.
Department of Chemistry, University of the Free State, P.O Box 339, Bloemfontein, Free State, South Africa.
Mol Divers. 2025 Sep 17. doi: 10.1007/s11030-025-11356-7.
The rise of drug-resistant Plasmodium falciparum necessitates novel antimalarial therapies. Leveraging the ConMedNP database, which includes over 3119 natural compounds from Central and West African medicinal plants, this study targets Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), a vital enzyme for parasite survival. Molecular docking of 2754 compounds revealed a mean binding affinity of 8.8032 kcal/mol (SD = 1.4 kcal/mol, median = 8.9 kcal/mol), with 75% outperforming artemether's reference affinity ( 8.0 kcal/mol). A Random Forest-based RaMQSAR model, trained on the docking data, achieved a test of 0.8321 (RMSE: 0.5294 kcal/mol) and reliable cross-validation (mean = 0.8461, SD = 0.0460). Validation against 19 known antimalarials showed predicted affinities from 7.0 to 10.5 kcal/mol, consistent with docking results. Top performers included RDC0118 ( 13.5 kcal/mol), RDC0119 ( 13.4 kcal/mol), and CA0001 ( 13.0 kcal/mol), all surpassing artemether. ADMET profiling indicated CA0001 and artemether as safer candidates (non-hepatotoxic, low environmental impact), while RDC0118 and RDC0119 exhibited potential mutagenicity and hepatotoxicity risks. MD simulations confirmed structural stability for both, with CA0001 showing compaction and transient H-bonds (0-3). DFT analysis highlighted CA0001's reactivity as a soft electrophile, contrasting with artemether's higher reactivity. This comprehensive approach integrating docking, QSAR, DFT, and MD positions CA0001 as a promising PfDHFR-TS inhibitor alongside artemether, with ConMedNP and predictive models guiding future experimental validation.
耐药性恶性疟原虫的出现使得新型抗疟疗法成为必要。本研究利用包含来自中非和西非药用植物的3119种以上天然化合物的ConMedNP数据库，将目标对准恶性疟原虫二氢叶酸还原酶-胸苷酸合成酶（PfDHFR-TS），这是寄生虫生存所必需的一种关键酶。对2754种化合物进行分子对接后发现，其平均结合亲和力为8.8032千卡/摩尔（标准差=1.4千卡/摩尔，中位数=8.9千卡/摩尔），其中75%的化合物的亲和力优于蒿甲醚的参考亲和力（8.0千卡/摩尔）。基于对接数据训练的基于随机森林的RaMQSAR模型，其测试值为0.8321（均方根误差：0.5294千卡/摩尔），并具有可靠的交叉验证（平均=0.8461，标准差=0.0460）。针对19种已知抗疟药物进行验证，结果显示预测亲和力在7.0至10.5千卡/摩尔之间，与对接结果一致。表现最佳的包括RDC0118（13.5千卡/摩尔）、RDC0119（13.4千卡/摩尔）和CA0001（13.0千卡/摩尔），均超过蒿甲醚。药物代谢动力学/药物毒性预测分析表明，CA0001和蒿甲醚是更安全的候选药物（无肝毒性，对环境影响小），而RDC0118和RDC0119存在潜在的致突变性和肝毒性风险。分子动力学模拟证实了两者的结构稳定性，CA0001表现出压缩和短暂氢键（0-3个）。密度泛函理论分析突出了CA0001作为软亲电试剂的反应性，这与蒿甲醚较高的反应性形成对比。这种整合对接、定量构效关系、密度泛函理论和分子动力学的综合方法将CA0001定位为与蒿甲醚一样有前景的PfDHFR-TS抑制剂，ConMedNP和预测模型将指导未来的实验验证。
