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1. Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket

Author

Koffi N’Guessan Placide Gabin Allangba, Mélalie Keita, Raymond Kre N’Guessan, Eugene Megnassan, Vladimir Frecer, and Stanislav Miertus

Subjects
falcipain-2, plasmodium falciparum, molecular modelling, qsar model, pharmacophore, virtual library, pharmacokinetics, Therapeutics. Pharmacology, RM1-950
Abstract

We report computer-aided design of new lactone–chalcone and isatin–chalcone (HLCIC) inhibitors of the falcipain-2 (PfFP-2). 3D models of 15 FP-2:HLCIC1-15 complexes with known observed activity (IC50exp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correlation between relative Gibbs free energy of enzyme:inhibitor complex formation (ΔΔGcom) and IC50exp: pIC50exp = −0.0236 × ΔΔGcom+5.082(#); R2 = 0.93. A 3D pharmacophore model (PH4) derived from the QSAR directed our effort to design novel HLCIC analogues. During the design, an initial virtual library of 2621440 HLCIC was focused down to 18288 drug-like compounds and finally, PH4 screened to identify 81 promising compounds. Thirty-three others were added from an intuitive substitution approach intended to fill better the enzyme S2 pocket. One hundred and fourteen theoretical IC50 (IC50pre) values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC50pre 100 times superior to that of the published most active training set inhibitor HLCIC1.

Published
2019
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2. Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket

Author

Melalie Keita, Raymond Kre N'Guessan, Stanislav Miertus, Vladimir Frecer, Koffi N'Guessan Placide Gabin Allangba, and Eugene Megnassan

Subjects
Isatin, Models, Molecular, Chalcone, Stereochemistry, Plasmodium falciparum, QSAR model, Quantitative Structure-Activity Relationship, 3d model, Cysteine Proteinase Inhibitors, chemistry.chemical_compound, Inhibitory Concentration 50, Lactones, Chalcones, virtual library, Catalytic Domain, Drug Discovery, Pharmacology, chemistry.chemical_classification, biology, pharmacophore, lcsh:RM1-950, Active site, General Medicine, biology.organism_classification, Cysteine protease, molecular modelling, Cysteine Endopeptidases, lcsh:Therapeutics. Pharmacology, Falcipain-2, chemistry, Drug Design, Molecular Probes, biology.protein, Computer-Aided Design, Thermodynamics, Pharmacophore, pharmacokinetics, Lactone, Research Paper
Abstract

We report computer-aided design of new lactone–chalcone and isatin–chalcone (HLCIC) inhibitors of the falcipain-2 (PfFP-2). 3D models of 15 FP-2:HLCIC1-15 complexes with known observed activity (IC 50 exp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correlation between relative Gibbs free energy of enzyme:inhibitor complex formation (ΔΔG com) and IC 50 exp: pIC 50 exp = −0.0236 × ΔΔG com+5.082(#); R 2 = 0.93. A 3D pharmacophore model (PH4) derived from the QSAR directed our effort to design novel HLCIC analogues. During the design, an initial virtual library of 2621440 HLCIC was focused down to 18288 drug-like compounds and finally, PH4 screened to identify 81 promising compounds. Thirty-three others were added from an intuitive substitution approach intended to fill better the enzyme S2 pocket. One hundred and fourteen theoretical IC50 (IC 50 pre) values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC 50 pre 100 times superior to that of the published most active training set inhibitor HLCIC1.

Published
2019

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