to be submitted

Abstract

Rationale The cysteine proteases falcipains are known to be importantly involved in hemoglobin catabolism with the crucial role to ultimately form the amino acids for the parasite growth [ ]. Among them falcipains-2 (FP2) have been largely studied but recently it was reported that inhibition of FP2 is not lethal for the parasite while inhibitors of FP3 are lethal for pf [ , ]. From the reported studies on these papain-like proteases inhibitors of FP2 are also potent against FP3 [2]. They are mostly vinyl sulfones lastly known to interact with proteasome [ ]. It becomes urgent to explore different area of the chemical space with the focus on potency and good pharmacokinetics profile. Objectives The main objective of this work is to analyze the feasibility of our in-house complexation methodology in the design of novel inhibitors of FP3. Methods pfFP3 – ADPNs complexes have been carefully prepared from X-rays crystal structure of pfFP3 – C1P (3BWK.pdb) [ ] for a training set of 7 ADPNs with known activity to build a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity in order to access the structural information necessary to design new low nanomolar azadipeptide nitriles. Results From Molecular Modeling investigations the agreement between CHARMM energy of interaction and Ki (pKi = - 0.4179×∆∆EMM + 1.8463; n = 7, R2 = 0.91, R2CV = 0.89, F = 52.4,  = 0.32). In the same way a correlation is observed between free energy of complexation (∆∆Gcompl) and Ki (pKi = -0.255×∆∆Gcompl + 1.8364; n = 6, R2 = 0.87, R2CV = 0.84, F = 26.7,  = 0.43) attests that more than 87% of the variation of the inhibitory activity data of the ADPNs can be explained on the basis of the ligand-receptor interactions with pfFP3. Conclusions The computational approach used here is able to provide structural information for the design of novel azadipeptide nitriles as reversible inhibitors of pfFP3. The training set used here is the unique available from literature till now [ ].