Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models

• DOI: 10.3390/scipharm89040044
• Publication Date: 2021-10-11T05:59:47Z
• Authors: Boris D. Bekono; Akori E. Esmel; Brice Dali; Fidele Ntie-Kang; Melalie Keita; Luc C. O. Owono; Eugene Megnassan
• Keywords: Peptidomimetic; Molecular mechanics; Molecular model; Cheminformatics

In this work, antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) Plasmodium falciparum (Pf) are proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models FP3-PEPx complexes known activities ( IC50exp) were prepared by in situ modification, based on mechanics implicit solvation to compute Gibbs free energies (GFE) inhibitor-FP3 formation. This resulted a quantitative structure–activity relationships (QSAR) model linear correlation between computed GFE (ΔΔGcom) experimentally measured IC50exp. Apart from relationship, ligand-based pharmacophore (PH4) novel PEP analogues where substitutions directed comparative analysis active site interactions was derived bound conformations PEPx. provided structural information useful for design virtual combinatorial libraries (VL), which virtually screened 3D-QSAR PH4. The end results predictive inhibitory falling within low nanomolar concentration range.