In silico design of Plasmodium falciparum cysteine protease falcipain 2 inhibitors with favorable pharmacokinetic profile

Abstract

We realized a virtual design of new azadipeptides nitriles (ADPNs) potential inhibitors of the cysteine protease falcipain 2 (FP2) protease inhibitors of Plasmodium falciparum (pf) by structure-based drug design (SBDD). From a series of 7 ADPNx with known FP2 inhibition potency, we constructed the FP2-ADPNx complexes by in situ modification of the X-rays crystal structure of FP2 in complex with epoxysuccinate E64 (pdb entry code: 3BPF). Out of then a one descriptor quantitative structure activity relationships (QSAR) model was built resulting in linear correlations between the gas phase computed enthalpy ∆∆HMM upon the FP2-ADPN complex formation and IC50exp (R square of 0.88; cross validated R square of 0.86 ; F-Test of 39.48). Thereafter taking into account the solvent effect and the loss of vibrational entropy of the inhibitor upon binding to the enzyme led to an improved QSAR model correlating the computed Gibbs free energy (GFE: ΔΔGcom) of FP2-ADPN complex formation and IC50exp (R square of 0.94 ; cross validated R square of 0.94 ; F-Test of 91.44). The estimated IC50pred from FP2 inhibition pharmacophore model derived from the QSAR model linearly correlates with IC50exp (R square of 0.99) bearing in this way structural inhibition information that served in the virtual screening of a combinatorial subset of a virtual library (VL) of more than 8000 ADPNs analogues. From the ADME focused VL, 68 best hit fit orally bioavailable analogues were selected and finally in silico evaluated with the GFE QSAR model to identify new powerful ADPNs with predicted IC50 reaching 0.5nM.