Malaria, primarily caused by Plasmodium falciparum, remained a major cause of mortality, particularly in tropical regions. The emergence of multidrug-resistant strains of Plasmodium falciparum has challenged global malaria control efforts, necessitating the search for new therapeutic agents. This study aims to investigate the molecular interactions between falcipain 2 and 3, key enzymes in P. falciparum haemoglobin degradation, and some selected compounds isolated from Combretum hypopilinum and other related Combretum species, using in silico molecular docking techniques. Twelve compounds were identified from the literature, their chemical structure drawn using ChemSketch software, followed by 3D optimization with Spartan software. Their structures geometrically optimized and docked against falcipain 2 and 3. The 3D crystal structures of falcipain 2 (PDB ID: 6JW9) and falcipain 3 (PDB ID: 3BwK) were retrieved from the Protein Data Bank, prepared using UCSF Chimera, and analyzed using AutoDock Vina. Binding affinities, root mean square deviations, and protein-ligand interactions were evaluated. The best poses were visualized with Discovery Studio Visualizer to obtain the nature of the interaction. Additionally, SWISSADME was used for ADMET analysis to assess drug-likeness and bioavailability of the compounds (pharmacokinetic profiles of the compound). The docking analysis revealed that most of the compounds exhibited stronger binding affinities compared to the native ligands, with binding energies ranging from -6.2 to -7.2 kcal/mol for falcipain 2 and -6.9 to -8.0 kcal/mol for falcipain 3. Compounds CP1, CP8, and CP10 demonstrated particularly strong interactions, suggesting their potentials as effective inhibitors. The root mean square deviation (RMSD) values all below 1.0 Å, confirmed precise fitting of the compounds within the active sites of the enzymes. These interactions were further supported by the formation of multiple hydrogen bonds with crucial active site residues essential for enzyme inhibition. Furthermore, ADMET analysis confirmed the drug-likeness and bioavailability of the majority of the compounds, w i t h m o s t d e m o n s t r a t i n g f a v o u r a b l e pharmacokinetic profile and no violations of Lipinski's rule of five, with CP6 and CP8 showing promising blood-brain barrier penetration potential. The findings suggested that the compounds, particularly those with strong binding energy and favourable pharmacokinetic properties, such as compound 1 (belamcanidin, (3,5 dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-4H-chromen-4-one), compound 8, combretin C (3-(â-D-xylopyranosyl)- 15á-hydroxycycloartan-28-oic acid), and compound 10, fragransinate (3?-(3?,4?-d i h y d r o x y - 5 - m e t h o x y p h e n y l ) p r o p y l heptadecanoate) may serve as promising antimalarial agents by inhibiting falcipain enzymes. Further experimental studies are necessary to validate these in silico predictions and elucidate the compounds' in vivo efficacy.
Abba et al. (Mon,) studied this question.