In Silico Development and Assessment of Hybrid Antimalarials as Falcipain Inhibitors

Abstract Background Malaria, caused by protozoan parasites of the genus Plasmodium , remains one of the most consequential infectious diseases globally, with Plasmodium falciparum responsible for the majority of severe cases and deaths, particularly in sub-Saharan Africa. Falcipain, a cysteine protease central to haemoglobin degradation within infected erythrocytes, represents an attractive and underexplored drug target because its inhibition directly disrupts the parasite’s nutrient acquisition and survival. Methods A library of 505 drugs used in the treatment of infectious diseases was retrieved from the Broad Institute Drug Repurposing Hub and downloaded from PubChem. All compounds were prepared using Open Babel and docked against the crystal structure of falcipain protease (PDB ID: 1YVB) using AutoDock Vina. Binding affinities were compared across five drug categories: antibiotics, antivirals, antifungals, antimalarials, and others. The two highest-affinity non-antimalarial compounds were paired with three established antimalarials to generate six hybrid molecules using an organic linker strategy via ChemSketch. Hybrid molecules were re-docked against falcipain, and their predicted ADMET properties, including lipophilicity (LogP, LogD7.4) and aqueous solubility (LogS), were evaluated computationally. Ligand–receptor interaction profiles were analysed in Discovery Studio. Results Of the 454 compounds successfully docked, Telithromycin (antibiotic, − 15.3 kcal/mol) and Doramectin (other antiparasitic, − 15.2 kcal/mol) showed the strongest binding affinities, followed by Amphotericin B (antifungal, − 13.4 kcal/mol) and Ledipasvir (antiviral, − 11.9 kcal/mol). Among antimalarials, Atovaquone recorded the highest affinity at − 11.0 kcal/mol. Six hybrid molecules were designed from Telithromycin and Doramectin in combination with Atovaquone, Mefloquine, and Artemether. TELI-ATOVA (Telithromycin–Atovaquone) exhibited the strongest binding affinity among hybrids (− 14.5 kcal/mol) with moderate lipophilicity and solubility. All six hybrids demonstrated higher binding affinities than any of their individual parent compounds. Interaction analysis revealed diverse profiles, including hydrogen bonding, van der Waals contacts, and pi–cation interactions. Conclusions The hybridisation of high-affinity non-antimalarial compounds with existing antimalarials yielded potent falcipain inhibitors, with TELI-ATOVA as the lead candidate. These findings support the utility of drug repurposing combined with rational hybrid design as a productive approach to antimalarial drug discovery. Experimental validation through enzyme inhibition assays, cytotoxicity studies, and in vitro parasite growth inhibition assays is warranted as the next step.