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

Abstract

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

Effects of some anti-ulcer and anti-inflammatory natural products on cyclooxygenase and lipoxygenase enzymes: insights from in silico analysis

“…To further understand the interactions of the ligands with the protein and ascertain the most important amino acids interacting with the target protein, the interaction energy (E int ) values for the docked complexes were computed using the Discovery Studio (BIOVIA, 2021), according to our previously published protocol (Bekono et al 2021). The non-bonded van der Waals and electrostatic interactions between each docked ligand and the protein binding site amino acid residues were computed for each synthesized compound, by use of the consistent force eld (Hagler and Lifson, 1974).…”