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Article

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

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Department of Physics, Ecole Normale Supérieure, University of Yaoundé I, Yaoundé CM-00237, Cameroon
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Laboratory of Fundamental and Applied Physics, University of Abobo-Adjame (now Nangui Abrogoua), Abidjan 02 BP 801, Côte d’Ivoire
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Department of Chemistry, Faculty of Science, University of Buea, Buea CM-00237, Cameroon
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Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany
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CEPAMOQ, Faculty of Science, University of Douala, Douala CM-00237, Cameroon
*
Authors to whom correspondence should be addressed.
Academic Editor: Helen D. Skaltsa
Sci. Pharm. 2021, 89(4), 44; https://doi.org/10.3390/scipharm89040044
Received: 12 July 2021 / Revised: 23 August 2021 / Accepted: 8 September 2021 / Published: 29 September 2021
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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.
Keywords: drug design; falcipain; malaria; peptidomimetics; Plasmodium falciparum; virtual screening; pharmacophore drug design; falcipain; malaria; peptidomimetics; Plasmodium falciparum; virtual screening; pharmacophore
MDPI and ACS Style

Bekono, B.D.; Esmel, A.E.; Dali, B.; Ntie-Kang, F.; Keita, M.; Owono, L.C.O.; Megnassan, E. Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models. Sci. Pharm. 2021, 89, 44. https://doi.org/10.3390/scipharm89040044

AMA Style

Bekono BD, Esmel AE, Dali B, Ntie-Kang F, Keita M, Owono LCO, Megnassan E. Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models. Scientia Pharmaceutica. 2021; 89(4):44. https://doi.org/10.3390/scipharm89040044

Chicago/Turabian Style

Bekono, Boris D., Akori E. Esmel, Brice Dali, Fidele Ntie-Kang, Melalie Keita, Luc C.O. Owono, and Eugene Megnassan. 2021. "Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models" Scientia Pharmaceutica 89, no. 4: 44. https://doi.org/10.3390/scipharm89040044

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