Abbreviations: FP2/FP3, falcipain 2/falcipain 3; pf, plasmodium falciparum; ADPN, azadipeptide nitrile; SBDD, structure-based drug design; E64, epoxysuccinate; PDB, protein data bank; QSAR, quantitative structure activity relationships; ΔΔG com , relative gibbs free energy change related to the enzyme-inhibitor complex formation; ΔΔH MM , relative enthalpic contribution to the Gibbs free energy change derived by molecular mechanics; ΔΔTS vib , relative entropic contribution of the inhibitor to the Gibbs free energy; ΔΔG sol , the relative solvation Gibbs free energy contribution to the gibbs free energy change; GFE, gibbs free energy; IC 50 exp , experimental inhibition constant ; VL, virtual library; ADME, adsorption distribution metabolism and excretion; ACTs, artemisinbased therapies; E, enzyme; DS, discovery studio (molecular modeling program); MOE, molecular operating environment (molecular modeling program); I, inhibitor; E:I, enzyme-inhibitor complex; SAR, structure-activity relationship; MM, molecular mechanics; CFF91, consistent force field 91; eint, interaction energy; 2D/3D, Two dimension/three dimension; RMSD, root mean square deviation; PH4, pharmacophoric hypotheses four features; Hypo, hypotheses; Et/Met/Ph, ethyl/methyl/phenyl; HB, hydrogen bond; vdW, van der waals; HOA, human oral absorption; nM, nanomolar J Anal Pharm Res. 2018;7(3):298-309.
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AbstractWe 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 ∆∆H MM upon the FP2-ADPN complex formation and IC 50 exp (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: ΔΔG com ) of FP2-ADPN complex formation and IC 50 exp (R square of 0.94 ; cross validated R square of 0.94 ; F-Test of 91.44). The estimated IC 50 pred from FP2 inhibition pharmacophore model derived from the QSAR model linearly correlates with IC 50 exp (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 IC 50 reaching 0.5nM.
Citation: Fagnidi YKH, Toi B, Megnassan E, et al. In silico de...
