Exploring Heterocyclic Compounds as Potent Malaria falcipain-2 Inhibitors versus Cathepsins: A Computational Approach

Abstract

Malaria, caused by Plasmodium parasites, leads to 400,000+ annual deaths, primarily affecting women and children in Asia and sub-Saharan Africa. Increasing medication resistance highlights the urgent need for better treatment strategies.

Falcipain-2, a cysteine protease in Plasmodium falciparum, is a crucial drug target but shares similarities with cathepsins, making selectivity essential in antimalarial therapy. Curcumin, a chalcone from turmeric, shows antimalarial properties but has bioavailability issues. This study explores modified curcumin analogs, specifically monocarbonyl curcumins, which lack the retro-aldol breakdown group. Computational approaches, including protein alignment, QSAR modeling, and in-silico techniques, were used to assess their bioavailability, solubility, stability, and toxicity.

QSAR modeling successfully predicted log% inhibitory activities of (E)-chalcones as falcipain-2 inhibitors using a nonlinear (ANN) method. The QSAR model was validated with external compounds, and statistical analysis confirmed its robustness. The GA-ANN model’s mean-squared errors (MSEs) were 0.045 for training and 0.063 for test sets. 28 new molecules (D1-D28) were designed and optimized, with predicted log% inhibition values. Docking studies of the most potent analogs (D9 & D10), curcumin, and standard drugs in falcipain-2 and cathepsin were conducted. Analog D9, with an affinity of -10.1 kcal/mol, showed strong selectivity for falcipain-2 over cathepsin. Further analyses evaluated bioavailability, solubility, stability, and toxicity for future in vitro and in vivo studies.