Combined CADD and Virtual Screening to Identify Novel Nonpeptidic Falcipain-2 Inhibitors.

Background: Plasmodium falciparum is the most dangerous and widespread diseasecausing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite's life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes.

Objective: Here, we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes.

Methods: We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the well-equilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio.

Results: We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, Pub- Chem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis.

Conclusion: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (Pub- Chem44138738), 6-bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (Pub- Chem 20983198), 2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem 20983081)and 2-[benzyl(methyl)amino]quinoline-3-carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.