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 FP protease inhibitors of Plasmodium falciparum pf by structure based drug design SBDD From a series of ADPNx with known FP inhibition potency we constructed the FP ADPNx complexes by in situ modification of the X rays crystal structure of FP in complex with epoxysuccinate E pdb entry code BPF 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 nbsp upon the FP ADPN complex formation and IC exp Rsquare of cross validated R square of F Test of 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 Delta Delta Gcom of FP ADPN complex formation and IC exp Rsquare of cross validated R square of F Test of The estimated IC pred from FP inhibition pharmacophore model derived from the QSAR model linearly correlates with IC exp Rsquare of 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 ADPNs analogues From the ADME focused VL best hit fit orally bioavailable analogues were selected and finally in silicoevaluated with the GFE QSAR model to identify new powerful ADPNs with predicted IC reaching nM