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

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 (IC50exp). 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 IC50exp. 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 IC50exp (pIC50exp = −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 IC50pre 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.

[1]  S. Miertus,et al.  Virtually Designed Triclosan‐Based Inhibitors of Enoyl‐Acyl Carrier Protein Reductase of Mycobacterium tuberculosis and of Plasmodium falciparum , 2015, Molecular informatics.

[2]  S. Miertus,et al.  Quantitative structure–activity relationships and design of thymine-like inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis with favourable pharmacokinetic profiles , 2014 .

[3]  S. Miertus,et al.  Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis , 2013, Tuberculosis research and treatment.

[4]  S. Cole,et al.  Towards a new tuberculosis drug: pyridomycin – nature's isoniazid , 2012, EMBO molecular medicine.

[5]  S. Miertus,et al.  Design of novel dihydroxynaphthoic acid inhibitors of Plasmodium falciparum lactate dehydrogenase. , 2012, Medicinal chemistry (Shariqah (United Arab Emirates)).

[6]  S. Miertus,et al.  Insight into Selectivity of Peptidomimetic Inhibitors with Modified Statine Core for Plasmepsin II of Plasmodium falciparum over Human Cathepsin D , 2012, Chemical Biology and Drug Design.

[7]  Peter J Tonge,et al.  A Slow, Tight Binding Inhibitor of InhA, the Enoyl-Acyl Carrier Protein Reductase from Mycobacterium tuberculosis* , 2010, The Journal of Biological Chemistry.

[8]  Joel S. Freundlich,et al.  Triclosan Derivatives: Towards Potent Inhibitors of Drug‐Sensitive and Drug‐Resistant Mycobacterium tuberculosis , 2009, ChemMedChem.

[9]  John P. Overington,et al.  Genomic-scale prioritization of drug targets: the TDR Targets database , 2008, Nature Reviews Drug Discovery.

[10]  S. Miertus,et al.  Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties. , 2008, Journal of molecular graphics & modelling.

[11]  Peter J Tonge,et al.  Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[12]  P. Ortiz de Montellano,et al.  Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. , 2007, Bioorganic & medicinal chemistry.

[13]  Vojo Deretic,et al.  Mechanisms of action of isoniazid , 2006, Molecular microbiology.

[14]  Robert Stroud,et al.  Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. , 2006, Journal of medicinal chemistry.

[15]  O. N. de Souza,et al.  Molecular dynamics simulation studies of the wild-type, I21V, and I16T mutants of isoniazid-resistant Mycobacterium tuberculosis enoyl reductase (InhA) in complex with NADH: toward the understanding of NADH-InhA different affinities. , 2005, Biophysical journal.

[16]  Jeremy C. Smith,et al.  Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal‐gas entropy correction? , 2002, J. Comput. Chem..

[17]  S. Miertus,et al.  Interactions of ligands with macromolecules: Rational design of specific inhibitors of aspartic protease of HIV‐1 , 2002 .

[18]  W. L. Jorgensen,et al.  Prediction of drug solubility from structure. , 2002, Advanced drug delivery reviews.

[19]  Emil Alexov,et al.  Rapid grid‐based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: Applications to the molecular systems and geometric objects , 2002, J. Comput. Chem..

[20]  Chandra Verma,et al.  Dissecting the Vibrational Entropy Change on Protein/Ligand Binding: Burial of a Water Molecule in Bovine Pancreatic Trypsin Inhibitor , 2001 .

[21]  James C. Sacchettini,et al.  Inactivation of the inhA-Encoded Fatty Acid Synthase II (FASII) Enoyl-Acyl Carrier Protein Reductase Induces Accumulation of the FASI End Products and Cell Lysis of Mycobacterium smegmatis , 2000, Journal of bacteriology.

[22]  W L Jorgensen,et al.  Prediction of drug solubility from Monte Carlo simulations. , 2000, Bioorganic & medicinal chemistry letters.

[23]  W. L. Jorgensen,et al.  Prediction of Properties from Simulations: Free Energies of Solvation in Hexadecane, Octanol, and Water , 2000 .

[24]  S. Miertus,et al.  Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants. , 1998, Drug design and discovery.

[25]  W. Jacobs,et al.  Mechanisms of isoniazid resistance in Mycobacterium tuberculosis: enzymatic characterization of enoyl reductase mutants identified in isoniazid-resistant clinical isolates. , 1998, The Journal of infectious diseases.

[26]  Robert A. Copeland,et al.  Estimating KI values for tight binding inhibitors from dose-response plots , 1995 .

[27]  J. Sacchettini,et al.  Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis , 1995, Science.

[28]  Ming-Jing Hwang,et al.  Derivation of class II force fields. I. Methodology and quantum force field for the alkyl functional group and alkane molecules , 1994, J. Comput. Chem..

[29]  Vladimir Frecer,et al.  Polarizable continuum model of solvation for biopolymers , 1992 .

[30]  Michael K. Gilson,et al.  The inclusion of electrostatic hydration energies in molecular mechanics calculations , 1991, J. Comput. Aided Mol. Des..

[31]  J. Tomasi,et al.  Electrostatic interaction of a solute with a continuum. A direct utilizaion of AB initio molecular potentials for the prevision of solvent effects , 1981 .

[32]  D. D. Yue,et al.  Theory of Electric Polarization , 1974 .

[33]  C. Dolea,et al.  World Health Organization , 1949, International Organization.

[34]  P. Wolschann,et al.  The structural requirement of direct InhA inhibitors for high potency against M. Tuberculosis based on computer aided molecular design , 2011 .

[35]  P. Willett,et al.  PHARMACOPHORE PERCEPTION , DEVELOPMENT , AND USE IN DRUG DESIGN , 2011 .

[36]  P. M. Dean,et al.  Molecular Similarity in Drug Design , 2007 .

[37]  J. W. Campbell,et al.  Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. , 2001, Annual review of microbiology.

[38]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[39]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..