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

• Main Authors: Boris D. Bekono (Author), Akori E. Esmel (Author), Brice Dali (Author), Fidele Ntie-Kang (Author), Melalie Keita (Author), Luc C. O. Owono (Author), Eugene Megnassan (Author)
• Format: Book
• Published: MDPI AG, 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/scipharm89040044; 2218-0532; 0036-8709
• Keywords: drug design; falcipain; malaria; peptidomimetics; <i>Plasmodium falciparum</i>; virtual screening; Pharmacy and materia medica; RS1-441
• Source: Scientia Pharmaceutica, Vol 89, Iss 4, p 44 (2021)

In this work, antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of <i>Plasmodium falciparum</i> (<i>Pf</i>) are proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of <i>Pf</i>FP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mrow><mrow><mo> </mo><mi>IC</mi></mrow></mrow><mrow><mn>50</mn></mrow><mrow><mi>exp</mi></mrow></msubsup></mrow></semantics></math></inline-formula>) 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 (ΔΔG_com) and the experimentally measured <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mrow><mrow><mo> </mo><mi>IC</mi></mrow></mrow><mrow><mn>50</mn></mrow><mrow><mi>exp</mi></mrow></msubsup></mrow></semantics></math></inline-formula>. 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.