Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles

Autor: Vladimir Frecer, Yao Thomas N'Guessan, Mawa Kone, Akori Esmel, Melalie Keita, Eugene Megnassan, Affiba Florance Kouassi, Stanislav Miertus
Rok vydání: 2015
Předmět:
Quantitative structure–activity relationship
Proline
Molecular model
in silico screening
medicine.drug_class
Enoyl-acyl carrier protein reductase
Molecular Sequence Data
QSAR model
Quantitative Structure-Activity Relationship
Carboxamide
Article
Catalysis
Pyrrolidine
Cyclic N-Oxides
Small Molecule Libraries
lcsh:Chemistry
Inorganic Chemistry
chemistry.chemical_compound
Bacterial Proteins
tuberculosis
pyrrolidine carboxamides
InhA inhibitors
molecular modeling
pharmacophore model
virtual combinatorial library
ADME properties
medicine
Amino Acid Sequence
Enzyme Inhibitors
Physical and Theoretical Chemistry
lcsh:QH301-705.5
Molecular Biology
Spectroscopy
ADME
Chemistry
Organic Chemistry
General Medicine
Combinatorial chemistry
Computer Science Applications
Enzyme binding
lcsh:Biology (General)
lcsh:QD1-999
Pharmacophore
Oxidoreductases
Zdroj: International Journal of Molecular Sciences, Vol 16, Iss 12, Pp 29744-29771 (2015)
International Journal of Molecular Sciences
Volume 16
Issue 12
Pages 29744-29771
International Journal of Molecular Sciences; Volume 16; Issue 12; Pages: 29744-29771
ISSN: 1422-0067
DOI: 10.3390/ijms161226196
Popis: 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.
Databáze: OpenAIRE
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