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 ( IC50exp) 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 (ΔΔGcom) and the experimentally measured IC50exp. 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.
Highlights
IntroductionThe treatment of malaria mainly depends on artemisinin-combined therapy (ACT), despite resistance to this combination
Two strategic approaches have been suggested in the search for new remedies against malaria; one focused on eliminating the parasite or preventing its contact with potential human hosts, and a second aimed at developing efficacious drugs to treat infected patients [1]
Weldon and co-workers synthesised 22 molecules, but not all showed detected biological activities against FP3 to be included in a quantitative structure–activity relationships (QSAR) study
Summary
The treatment of malaria mainly depends on ACT, despite resistance to this combination This suggests the need for industry–academia partnerships for the search of new antimalarials which act via alternative modes of action. Two strategic approaches have been suggested in the search for new remedies against malaria; one focused on eliminating the parasite or preventing its contact with potential human hosts, and a second aimed at developing efficacious drugs to treat infected patients [1]. The latter is often aimed at the inhibition of a therapeutic target, often a vital enzyme involved in the parasite’s life cycle. This often requires the search for or the design of new molecules capable of binding in a specific manner to known parasite vital enzymes
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