title: Virtually Designed Triclosan-Based Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis and of Plasmodium falciparum.
abstract: We report here new chemical structures of predicted nanomolar triclosan-based inhibitors (TCLs) of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) virtually proposed by computer-assisted molecular design. 3D models of InhA-TCL complexes were prepared by in situ modifications of the reference crystal structure (PDB entry 1P45) for a training set of 15 TCLs with known InhA inhibitory activities. A QSAR model was built leading to linear correlation between the calculated free energies of complexation (ΔΔGcom ) and experimental values IC50 (exp) : pIC50 =-0.0657×ΔΔGcom +3.0502, R(2) =0.96. In addition, ligand-based quantitative pharmacophore model (PH4) was built from bound conformations of the training set compounds and confirmed the correlation between molecular models and observed activities: pIC50 (exp=) 0.8929×pIC50 (pre) -0.441, R(2) =0.95. Structural information from both models helped us to propose new TCL analogues. A virtual library of TCLs with known predicted activities against enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) was evaluated, revealing dual target TCLs. Moreover, analysis of binding site interactions suggested enriching substitutions, which led to more potent TCLs with predicted pIC50 (pre) as low as 7 nM. The computational approach, which used both free energy estimated from molecular modeling and 3D-QSAR pharmacophore model, was helpful in virtually proposing the dual-targeted drugs and provided valuable information for the design of novel potential antituberculotic agents.
authors.affiliation: University of Yaoundé I, Advanced Teacher Training College, Laboratory for Simulation and Molecular Biophysics, P.O. Box 47 Yaoundé, Cameroon.|University of Douala, Centre for Atomic Molecular Physics and Quantum Optics (CEPAMOQ), P.O. Box 8580 Douala, Cameroon.|International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008.
authors.forename: Luc C
authors.initials: LC
authors.lastname: Owono Owono
authors.affiliation: University of Douala, Centre for Atomic Molecular Physics and Quantum Optics (CEPAMOQ), P.O. Box 8580 Douala, Cameroon.|International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008.|University of Buea, Chemical and Bioactivity Information Centre, Department of Chemistry, P.O. Box 63, Buea, Cameroon.
authors.forename: Fidele
authors.initials: F
authors.lastname: Ntie-Kang
authors.affiliation: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008.|University of Abobo Adjamé, UFR SFA, Laboratoire de Physique Fondamentale et Appliquée, 02 BP 801, Abidjan 02, Cote D'Ivoire.
authors.forename: Melalie
authors.initials: M
authors.lastname: Keita
authors.affiliation: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008. megnase@yahoo.com.|University of Abobo Adjamé, UFR SFA, Laboratoire de Physique Fondamentale et Appliquée, 02 BP 801, Abidjan 02, Cote D'Ivoire. megnase@yahoo.com.
authors.forename: Eugene
authors.initials: E
authors.lastname: Megnassan
authors.affiliation: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008.|Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University, SK-83232 Bratislava, Slovakia.|International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
authors.affiliation: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste, I-34012, Italy phone:+22502363008.|International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia.|Faculty of Natural Sciences, University of Ss. Cyril and Methodius, SK-91701 Trnava, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014260:Triclosan / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C085257:InhA protein, Mycobacterium
keywords: In silico screening; InhA; Malaria; Pharmacophore model; QSAR model; Triclosan derivatives; Tuberculosis