Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket
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...
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Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2018.1564288 |
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doaj-81ff42822d174810b7d71172ba3115fa2020-11-25T01:16:35ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-0134154756110.1080/14756366.2018.15642881564288Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocketKoffi N’Guessan Placide Gabin Allangba0Mélalie Keita1Raymond Kre N’Guessan2Eugene Megnassan3Vladimir Frecer4Stanislav Miertus5University of Abobo Adjamé (now Nangui Abrogoua)University of Abobo Adjamé (now Nangui Abrogoua)University of Abobo Adjamé (now Nangui Abrogoua)University of Abobo Adjamé (now Nangui Abrogoua)ICS-UNIDOICS-UNIDOWe 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.http://dx.doi.org/10.1080/14756366.2018.1564288falcipain-2plasmodium falciparummolecular modellingqsar modelpharmacophorevirtual librarypharmacokinetics |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Koffi N’Guessan Placide Gabin Allangba Mélalie Keita Raymond Kre N’Guessan Eugene Megnassan Vladimir Frecer Stanislav Miertus |
| spellingShingle |
Koffi N’Guessan Placide Gabin Allangba Mélalie Keita Raymond Kre N’Guessan Eugene Megnassan Vladimir Frecer Stanislav Miertus 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 falcipain-2 plasmodium falciparum molecular modelling qsar model pharmacophore virtual library pharmacokinetics |
| author_facet |
Koffi N’Guessan Placide Gabin Allangba Mélalie Keita Raymond Kre N’Guessan Eugene Megnassan Vladimir Frecer Stanislav Miertus |
| author_sort |
Koffi N’Guessan Placide Gabin Allangba |
| title |
Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket |
| title_short |
Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket |
| title_full |
Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket |
| title_fullStr |
Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket |
| title_full_unstemmed |
Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket |
| title_sort |
virtual design of novel plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the s2 active site pocket |
| publisher |
Taylor & Francis Group |
| series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
| issn |
1475-6366 1475-6374 |
| publishDate |
2019-01-01 |
| description |
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. |
| topic |
falcipain-2 plasmodium falciparum molecular modelling qsar model pharmacophore virtual library pharmacokinetics |
| url |
http://dx.doi.org/10.1080/14756366.2018.1564288 |
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