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

Koffi N'Guessan Placide Gabin Allangba; Mélalie Keita; Raymond Kre N'Guessan; Eugene Megnassan; Vladimir Frecer; Stanislav Miertus

doi:10.1080/14756366.2018.1564288

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

J Enzyme Inhib Med Chem. 2019 Dec;34(1):547-561. doi: 10.1080/14756366.2018.1564288.

Authors

Koffi N'Guessan Placide Gabin Allangba¹, Mélalie Keita¹, Raymond Kre N'Guessan¹, Eugene Megnassan^{1

2

3}, Vladimir Frecer^{3

4

5}, Stanislav Miertus^{3

5

6}

Affiliations

¹ a Laboratoire de Physique Fondamentale et Appliquée (LPFA) , University of Abobo Adjamé (now Nangui Abrogoua) , Abidjan , Côte d'Ivoire.
² b Laboratoire de Chimie Organique Structurale et Théorique , University of Cocody (now Felix Houphouët Boigny) , Abidjan , Côte d'Ivoire.
³ c ICS-UNIDO , Trieste , Italy.
⁴ d Faculty of Pharmacy , Comenius University in Bratislava , Bratislava , Slovakia.
⁵ e International Centre for Applied Research and Sustainable Technology , Bratislava , Slovakia.
⁶ f Faculty of Natural Sciences , University of SS. Cyril and Methodius , Trnava , Slovakia.

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 (IC₅₀^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 IC₅₀^exp: pIC₅₀^exp = -0.0236 × ΔΔG_com+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 (IC₅₀^pre) values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC₅₀^pre 100 times superior to that of the published most active training set inhibitor HLCIC1.

Keywords: Falcipain-2; Plasmodium falciparum; QSAR model; molecular modelling; pharmacokinetics; pharmacophore; virtual library.

MeSH terms

Catalytic Domain
Chalcones / chemistry*
Chalcones / pharmacology
Computer-Aided Design
Cysteine Endopeptidases / drug effects*
Cysteine Endopeptidases / metabolism
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / pharmacokinetics
Cysteine Proteinase Inhibitors / pharmacology*
Drug Design*
Inhibitory Concentration 50
Isatin / chemistry*
Isatin / pharmacology
Lactones / chemistry*
Lactones / pharmacology
Models, Molecular
Molecular Probes
Plasmodium falciparum / enzymology*
Quantitative Structure-Activity Relationship
Thermodynamics

Substances

Chalcones
Cysteine Proteinase Inhibitors
Lactones
Molecular Probes
Isatin
Cysteine Endopeptidases
falcipain 2

Grants and funding

Financial support from the Slovak Research and Development Agency [APVV-15–0111, APVV-14–0294 and APVV-17–0239] and Granting Agency of Slovak Ministry of Education and Slovak Academy of Sciences [VEGA 1/0228/17], are gratefully acknowledged.