Abstract:
Falcipain-2 (FP-2) and falcipain-3 (FP-3), haemoglobin-degrading enzymes in Plasmodium
falciparum, are validated drug targets for the development of effective inhibitors against
malaria. However, no commercial drug-targeting falcipains has been developed despite
their central role in the life cycle of the parasites. In this work, in silico approaches are used
to identify key structural elements that control the binding and selectivity of a diverse set of
non-peptidic compounds onto FP-2, FP-3 and homologues from other Plasmodium species
as well as human cathepsins. Hotspot residues and the underlying non-covalent
interactions, important for the binding of ligands, are identified by interaction fingerprint
analysis between the proteases and 2-cyanopyridine derivatives (best hits). It is observed
that the size and chemical type of substituent groups within 2-cyanopyridine derivatives
determine the strength of protein–ligand interactions. This research presents novel results
that can further be exploited in the structure-based molecular-guided design of more
potent antimalarial drugs.
