Singh Varsha K, Sahu Niharika, Kesheri Minu, Kanchan Swarna, Kumar Amit, Sinha Rajeshwar P
Laboratory of Photobiology and Molecular Microbiology, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
Comput Biol Med. 2025 Sep;196(Pt B):110815. doi: 10.1016/j.compbiomed.2025.110815. Epub 2025 Jul 21.
A cysteine protease, falcipain-2 (FP-2) belonging to papain family is an important haemoglobinase of erythrocytic parasite Plasmodium falciparum. FP2 inhibitors mainly functions by blocking haemoglobin hydrolysis thereby inhibiting parasite development, promoting FP2 as an applicable target to combat malaria. A library of MAAs was prepared and screened as potential FP2 inhibitors. E-64 was used as a reference inhibitor of FP2 for its comparability with the screened hits.
Molecular docking analysis was conducted on twenty-seven compounds to assess their potential interactions with FP2. Following the docking analysis, an in-silico exploration of ADME characteristics, along with an evaluation of oral toxicity, were performed for these compounds.
Out of twenty-seven screened compounds, seven showed favorable properties with no toxicity. The compounds exhibited favorable binding as evident from the docking score, and possess high stability as elucidated by the RMSD, RMSF and RoG plots. The top two hit compounds with maximum drug score, i.e., shinorine and mycosporine-hydroxyglutamicol were selected for simulation studies which determines the robustness of protein-ligand complex.
The results derived from these studies on FP2 inhibition by MAAs suggest that these metabolites possess a significant antimalarial activity by impeding the target enzyme's active site, thereby providing significant insights in playing crucial role in the emergence of novel drugs to combat malaria.
半胱氨酸蛋白酶恶性疟原虫蛋白酶-2（FP-2）属于木瓜蛋白酶家族，是恶性疟原虫红细胞内寄生虫的一种重要血红蛋白酶。FP2抑制剂主要通过阻断血红蛋白水解来发挥作用，从而抑制寄生虫发育，使FP2成为对抗疟疾的一个适用靶点。制备并筛选了一组MAAs作为潜在的FP2抑制剂。E-64因其与筛选出的活性化合物具有可比性，被用作FP2的参考抑制剂。
对27种化合物进行分子对接分析，以评估它们与FP2的潜在相互作用。对接分析后，对这些化合物进行了ADME特性的计算机模拟探索以及口服毒性评估。
在筛选出的27种化合物中，有7种表现出良好的性质且无毒性。从对接分数可以明显看出这些化合物具有良好的结合能力，并且如RMSD、RMSF和RoG图所示具有高稳定性。选择药物分数最高的前两种活性化合物，即紫菜碱和霉菌胞嘧啶-羟基谷氨酸进行模拟研究，以确定蛋白质-配体复合物的稳定性。
这些关于MAAs对FP2抑制作用的研究结果表明，这些代谢产物通过阻碍靶酶的活性位点具有显著的抗疟活性，从而为新型抗疟药物的研发提供了重要见解。
