Falcipain-2 (FP-2) and Falcipain-3 (FP-3) are major hemoglobinases of P. falciparum, essential for the growth of protozoa and are validated targets for the development of antimalarial chemotherapy. A number of potent inhibitors of FP-2 were discovered either based on the knowledge of substrate-binding sites or by virtual screening of compound libraries. However, the resulting SAR of the identified hits was unusually steep in some cases and could not be explained by a traditional analysis of the interactions. To gain insights, a statistical thermodynamic analysis of explicit solvent in the ligand binding domain of FP-2 and -3 was performed that explained some of the complex trends in the SAR. Furthermore, the reduced potency of a subset of FP-2 hits was elucidated using quantum mechanics calculations that showed reduced reactivity of the reactive center of these hits. The present study highlights the importance of considering energetic contributors to binding beyond traditional interactions.

Falcipain-2 inhibitors: Structure-based drug design, solvent thermodynamics, reactivity analysis

243rd National Meeting (2012)

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