Acyl Carrier Protein Reductase Inhibitors Research Articles

Molecular Modeling of Enoyl Acyl Carrier Protein Reductase Inhibitors for Mycobacterium tuberculosis and their Pharmacokinetic Predictions

Tuberculosis (TB) is a deep public health concern worldwide worsened by reported multi drugresistant (MDR) and extensively drug- resistant (XDR) stralins of Mycobacterium tuberculosis, the causative agent of the disease. A new class of thiadiazole inhibitors were reported to inhibit the enoyl-acyl transporter protein reductase (InhA) of Mycobacterium tuberculosis (MTb). We performed here the computer-aided molecular design of novel thiadiazole (TDZ) inhibitors of InhA by in situ modifying the reference crystal structure of (S)-1-(5-((1-(2,6-difluorobenzyl)-1 H-pyrazol-3yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)ethanol-InhA (PDB code: 4BQP). Thus a training set of 15 hybrids with known inhibition potency \(\left(\mathrm{IC}_{50}^{\exp }\right)\) was selected to establish a onedescriptor quantitative structure-activity relationship (QSAR) model resulting in a linear correlation between the Gibbs free energy (GFE) during the formation of the InhA-TDZ complex and \(\mathrm{IC}_{50}^{\mathrm{exp}}\left(\mathrm{plC} \mathrm{C}_{50} \exp ==-0.29 \mathrm{x} \Delta \Delta \mathrm{G}_{\mathrm{com}}+8.13 ; \mathrm{n}=15 ; \mathrm{R}^2=0.92, \mathrm{R}^2{ }_{\mathrm{xv}}=0.91 ;\right.\) F-test of \(142.6 ; \sigma=0.21 ; \alpha>\) \(\left.95 \% ; R^2-R_{x v}^2=0.01\right)\). The 3D pharmacophore model \((\mathrm{PH} 4)\) generated from the active conformations of TDZs ( \(\mathrm{pIC}_{50}^{\mathrm{exp}}=0.93 \times \mathrm{pIC}_{50}^{\text {pred }}+0.47 ; \mathrm{n}=15 ; \mathrm{R}^2=0.97 ; \mathrm{R}_{\mathrm{xv}}=0.94 ;\) F-test of \(215.45 ; \sigma=0.17 ; \alpha>98 \% ; R^2-R_{x v}^2=0.03\) ) served as a virtual screening tool for new analogs from a virtual library (VL). The combination of molecular modeling and \(\mathrm{PH} 4\) in silico screening of (\(\mathrm{VL}\)) resulted in the identification of novel potent antitubercular agent candidates with favorable pharmacokinetic profiles of which the six best hits predicted inhibitory potencies \(\mathrm{IC}_{50}^{\text {pre }}\) in the sub nanomolar range \((0.1-0.2 \mathrm{nM})\).

In silico evaluation of natural bioactive compounds as Mycobacterium leprae enoyl acyl carrier protein reductase inhibitors

Background and Objectives:
 The present study was designed to assess the antileprotic effectiveness of some bioactive natural compounds towards enoyl acyl carrier protein reductase inhibition. Leprosy still constitutes a global pandemic in spite of long years of discovery. The current therapy option is multi-drug treatment using a combination of Dapsone, Rifampicin and Clofazimine. However, mycobacterium leprae counteracted by mutating the drug targets which necessitates the search for novel targets. One such target is enoyl acyl carrier protein reductase that mediates the fatty acid biosynthesis.
 Materials and Methods:
 Multiple (14) ligands of natural origin were drawn from PubChem database and their ADMET parameters were preicted using ADMETLab 2.0 webserver. After, the ligands were docked against the enzyme (PDB ID: 2NTV) at its active site using iGEMDOCK software.
 Results:
 ADMET parameters of the tested ligands proven to be accepted by Lipinski's rule of five except for two ligands. Furthermore, molecular docking results revealed that all of the tested compounds showed better binding energy than the reference drug Dapsone. The best of which was silymarin.
 Conclusion:
 The tested natural ligands have the capability to control M.leprae.

Design, Synthesis and Biological Investigation of Some Novel Quinazolin-4(3H)-One Tethered 1, 3, 4-Thiadiazole-Thiol Motifs as Direct Enoyl Acyl Carrier Protein Reductase Inhibitors

Aims: In this study was two noteworthy pharmacophores quinazolin-4(3H)-one and 1,3,4-thiadiazole through methylene bridge were utilized to design, synthesize and characterize some novel 2-methyl quinazolin-4(3H)-one and 6-chloro-2-methyl quinazolin-4(3H)-one tethered S-substituted-1,3,4-thiadiazole-thiol structural analogs respectively as direct Mycobacterium Tuberculosis (MTB) enoyl acyl carrier protein reductase (InhA) inhibitors.
 Study Design: Design of structural analogs of quinazolin-4(3H)-one tethered 1,3,4-thiadiazole-thiol through methylene bridge by functional group modifications in core scaffold followed by computational studies to select promising compounds. Synthesis of some novel compounds, structural characterization and screening of biological activity of the same.
 Methodology: The molecular docking of designed compunds was carried out using schrodinger Glide XP into the active site of MTB InhA with protein data bank code (PDB ID: 2H7M). The interactions were evaluated based on the glide G score compared with reference standard isoniazid. Ten new compounds 7(A1-A10) were synthesized, characterized and screened for their in-vitro antitubercular activity by Microplate Almar Blue Assay (MABA) method followed by cytotoxicity evaluation of compounds 7A4 and 7A10 using Vero cell line.
 Results: All the designed compounds of series 7(A1-A10) had drug-like characteristics and were non-toxic to normal cells. In the molecular docking studies, compounds 7A4, 7A5, and 7A10 demonstrated strong binding affinity in the active region of MTB InhA protein and retained necessary amino acid interaction, similar to co-crystal 2H7M. Synthesized compounds 7(A1-A10) were found to have good antitubercular activity. Out of the series the compounds 7A4 and 7A10 were found to possess excellent antitubercular activity equipotent to reference standard streptomycin with minimum inhibitory concentration (MIC) value of 6.25µg/ml. The cytotoxic potential of compounds 7A4 and 7A10 showed remarkable selectivity index against Vero cell line.
 Conclusion: The findings of this study highlights the importance of tethering two pharmacophoric motifs in one compound to develop novel antitubercular agents that can be exploited as promising leads as direct InhA inhibitors.

Molecular Docking and Three‐Dimensional Quantitative Structure–Activity Relationships for Antitubercular Pyrimidine Derivatives

Enoyl Acyl Carrier Protein (ACP) Reductase, a key enzyme, which catalyzes the last reductive step of fatty acid biosynthesis and it, is one of the key enzymes for the development of antitubercular agents. In this pursuit, molecular docking and 3D-QSAR studies (CoMFA and CoMSIA) have been performed on a series of pyrimidine derivatives (29 compounds) to understand the binding sites, interactions to improve over the existing leads in terms of improved biological and physico-chemical properties. Molecular docking was performed on a protein InhA (T2A mutant) (PDB ID: 5OIR) using the Surflex-Dock suite available in SYBYL-X 2.1.1 (Tripose Inc., USA). In addition, 3D-QSAR studies have been performed to validate the models using the data set, which was segregated into training and test set by using the Diversity and Dissimilarity method. Structural features required for the prediction of better inhibitory potency was generated in the form of contour maps from the CoMFA and CoMSIA models (Steric, Electrostatic, Hydrophobicity, H-bond donor and acceptor maps) and predicted values for r2 = 0.966, q2 = 0.22 for the CoMFA model and r2 = 0.925, q2 = 0.576 for the CoMSIA model. From this study, it is observed that interaction with amino acid residues TYR158, MET199, MET161, GLY96, and PHE97 are important for the activity that helped to predict SARs by providing important structural features. Both the models were good in understanding the specific activity of some of the compounds that will facilitate to develop new types of Enoyl ACP reductase inhibitors.

Enoyl Acyl Carrier Protein Reductase Inhibitors: An Emerging Target

Enoyl Acyl Carrier Protein Reductase Inhibitors: An Emerging Target

Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors

Purpose: To perform a virtual screening for a set of drug-like ligand library against the Staphylococcus aureus enoyl acyl carrier protein reductase, saFabI.Methods: The virtual screening was conducted based on a previously validated pharmacophoreconstrained docking. Consequently, the top list obtained was filtered using visual inspection where forty compounds were selected for experimental testing using disk-diffusion test and broth dilution method. The hits obtained were checked for their toxicity against human fibroblasts cell lines.Results: Three compounds were active against Staphylococcus aureus and other tested gram-positive bacteria. However, no significant inhibitory activity (p < 0.05) was detected against Escherichia coli or Candida albicans. The minimum inhibitory concentration (MIC) values for the most active compounds were identified using the broth dilution method; all of them exhibited inhibitory activity within micromolar range.The docking results showed that the hits obtained exhibited a small size with a nice binding mode to saFabI enzyme, forming the important interactions with the key residues. Furthermore, the best three hits demonstrated good safety profile as they did not show any significant toxicity against human fibroblast cell line.Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents.Keywords: Enoyl acyl carrier protein reductase, saFabI, Antibacterial agents, Docking, Constraint, Virtual screening Tropical Journal of Pharmaceutical

Development of gallic acid formazans as novel enoyl acyl carrier protein reductase inhibitors for the treatment of tuberculosis

The enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel antitubercular agents. A series of gallic acid formazans, were computationally designed and docked into the active site of InhA to understand their binding mode and potential to inhibit InhA. Nine compounds from the designed series were identified as potential InhA inhibitors, on the basis of good Glide score. These compounds were synthesized in the laboratory and evaluated for in vitro antitubercular activity against drug-sensitive and multi-drug resistant strains of MTB. Out of nine compounds, three compounds exhibited the most promising MIC of <2μM against the sensitive strain of MTB, H37Rv. The compounds were evaluated against five resistant strains of MTB. Most of the compounds exhibited activity superior to the standard, linezolid, against all these resistant strains. The mechanism of action of these compounds was concluded to be InhA inhibition, through InhA enzyme inhibition study. Insignificant cytotoxicity of these compounds was observed on RAW 264.7 cell line. Inactivity of all these compounds against gram positive and gram negative bacteria indicated their specificity against MTB. The compounds were further analyzed for ADME properties and showed potential as good oral drug candidates. The results clearly identified some novel, selective and specific InhA inhibitors against sensitive and resistant strains of MTB.

3D-QSAR studies of quinoline Schiff bases as enoyl acyl carrier protein reductase inhibitors

3D-QSAR studies of quinoline Schiff bases as enoyl acyl carrier protein reductase inhibitors

A Rational Approach to Identify Inhibitors of Mycobacterium tuberculosis Enoyl Acyl Carrier Protein Reductase

Mycobacterial enoyl acyl carrier protein (ACP) reductase is an attractive target for focused design of novel antitubercular agents. Structural information available on enoyl-ACP reductase in complex with different ligands was used to generate receptor-based pharmacophore model in Discovery Studio (DS). In parallel, pharmacophore models were also generated using ligand-based approach (HypoGen module in DS). Statistically significant models were generated (r(2) = 0.85) which were found to be predictive as indicated from internal and external cross-validations. The model was used as a query tool to search Zinc and Maybridge databases to identify lead compounds and predict their activity in silico. Database searching retrieved many potential lead compounds having better estimated IC50 values than the training set compounds. These compounds were then evaluated for their drug-likeliness and pharmacokinetic properties using DS. Few selected compounds were then docked into the crystal structure of enoyl-ACP reductase using Dock 6.5. Most compounds were found to have high score values, which was found to be consistent with the results from pharmacophore mapping. Additionally, molecular docking provided useful insights into the nature of binding of the identified hit molecules. In summary, we show a useful strategy employing ligand- and structure-based approaches (pharmacophore modeling coupled with molecular docking) to identify new enoyl- ACP reductase inhibitors for antimycobacterial chemotherapy.

Enoyl acyl carrier protein reductase inhibitors: a patent review (2006 – 2010)

Introduction: Bacterial enoyl acyl carrier protein reductase (ENR) specificity reduces the double bond in enoyl thioester substrates in the final enzymatic step of the elongation cycle of the fatty acid synthase-II pathway. Its function is essential for bacterial organism survival, making it an attractive target for the development of novel antibiotics. The structural features and therapeutic potential of this enzyme have stimulated the rational design of ENR inhibitors, and important progress has been achieved to date.Areas covered: This review describes recent advances made in the search for ENR inhibitors, as reflected by patent applications filed from 2006 to 2010, together with an overview of the relevant literature. The first section of this paper provides a background of the biology of ENR, followed by a description of its structure and function. The main section describes the substrate specificities for ENR, and the structure-based rational design of patent inhibitors originating from different companies and academic groups.Expert opinion: The increase in the number of ENR inhibitors bodes well for the development of new therapeutics against multidrug-resistant bacteria. The challenge is now to improve the pharmacokinetic parameters of these inhibitors and translate them into clinical studies.