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

Journal of Enzyme Inhibition and Medicinal Chemistry

Vladimir Frecer¹  Stanislav Miertus²  Raymond Kre N’Guessan³  Koffi N’Guessan Placide Gabin Allangba³  Mélalie Keita³  Eugene Megnassan⁴ 

[1] ICS-UNIDO, Trieste, Italy;Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia;International Centre for Applied Research and Sustainable Technology, Bratislava, Slovakia;ICS-UNIDO, Trieste, Italy;International Centre for Applied Research and Sustainable Technology, Bratislava, Slovakia;Faculty of Natural Sciences, University of SS. Cyril and Methodius, Trnava, Slovaki;Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire;Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire;Laboratoire de Chimie Organique Structurale et Théorique, University of Cocody (now Felix Houphouët Boigny), Abidjan, Côte d'Ivoire;ICS-UNIDO, Trieste, Italy;

关键词: Falcipain-2;    Plasmodium falciparum;    molecular modelling;    QSAR model;    pharmacophore;    virtual library;    pharmacokinetics;   

DOI  :  10.1080/14756366.2018.1564288

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY