title: Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles.
abstract: We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50(exp)). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50(exp). Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50(exp) (pIC50(exp) = -0.1552·ΔΔGcom + 5.0448, R² = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50(pre) reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.
authors.affiliation: Laboratoire de Physique Fondamentale et Appliquée, University of Abobo Adjamé-Nangui Abrogoua, Autoroute d'Abobo, Abidjan 02, Cote D'Ivoire. oreli060@yahoo.fr.
authors.forename: Affiba Florance
authors.initials: AF
authors.lastname: Kouassi
authors.affiliation: Laboratoire de Chimie Organique et des Substances Naturelles, University of Cocody-Felix Houphouët-Boigny, Avenue de l'Université, Abidjan 22, Cote D'Ivoire. kone_m2001@yahoo.fr.|International Centre for Science and High Technology, UNIDO, Area Science Park, Trieste I-34012, Italy. kone_m2001@yahoo.fr.
authors.forename: Mawa
authors.initials: M
authors.lastname: Kone
authors.affiliation: Laboratoire de Physique Fondamentale et Appliquée, University of Abobo Adjamé-Nangui Abrogoua, Autoroute d'Abobo, Abidjan 02, Cote D'Ivoire. keitamelalie@yahoo.fr.|International Centre for Science and High Technology, UNIDO, Area Science Park, Trieste I-34012, Italy. keitamelalie@yahoo.fr.
authors.forename: Melalie
authors.initials: M
authors.lastname: Keita
authors.affiliation: Laboratoire de Physique Fondamentale et Appliquée, University of Abobo Adjamé-Nangui Abrogoua, Autoroute d'Abobo, Abidjan 02, Cote D'Ivoire. elvicee@yahoo.fr.
authors.forename: Akori
authors.initials: A
authors.lastname: Esmel
authors.affiliation: Laboratoire de Physique Fondamentale et Appliquée, University of Abobo Adjamé-Nangui Abrogoua, Autoroute d'Abobo, Abidjan 02, Cote D'Ivoire. megnase@yahoo.com.|Laboratoire de Chimie Organique et des Substances Naturelles, University of Cocody-Felix Houphouët-Boigny, Avenue de l'Université, Abidjan 22, Cote D'Ivoire. megnase@yahoo.com.|International Centre for Science and High Technology, UNIDO, Area Science Park, Trieste I-34012, Italy. megnase@yahoo.com.
authors.forename: Eugene
authors.initials: E
authors.lastname: Megnassan
authors.affiliation: Laboratoire de Chimie Organique et des Substances Naturelles, University of Cocody-Felix Houphouët-Boigny, Avenue de l'Université, Abidjan 22, Cote D'Ivoire. nguessanyat@yahoo.fr.
authors.forename: Yao Thomas
authors.initials: YT
authors.lastname: N'Guessan
authors.affiliation: International Centre for Science and High Technology, UNIDO, Area Science Park, Trieste I-34012, Italy. frecer@fpharm.uniba.sk.|Faculty of Pharmacy, Comenius University in Bratislava, Bratislava SK-83232, Slovakia. frecer@fpharm.uniba.sk.|International Centre for Applied Research and Sustainable Technology, Bratislava SK-84104, Slovakia. frecer@fpharm.uniba.sk.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
authors.affiliation: International Centre for Science and High Technology, UNIDO, Area Science Park, Trieste I-34012, Italy. stanislav.miertus@icarst.org.|International Centre for Applied Research and Sustainable Technology, Bratislava SK-84104, Slovakia. stanislav.miertus@icarst.org.|Faculty of Natural Sciences, University of SS. Cyril and Methodius, Trnava SK-91701, Slovakia. stanislav.miertus@icarst.org.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C585850:3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; D001426:Bacterial Proteins; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D011392:Proline; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; C056291:prolinamide
keywords: ADME properties; InhA inhibitors; QSAR model; in silico screening; molecular modeling; pharmacophore model; pyrrolidine carboxamides; tuberculosis; virtual combinatorial library