Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors

Background: TGF-β signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-β inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity. Objective: The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-β inhibitors synthesized. Methods: Two series of 3-substituted-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalinyl-6-yl)- 1H-imidazol-2-yl)methylene)-2-thioxothiazolin-4-ones (12a–h and 13a–e) were synthesized and evaluated for their ALK5 inhibitory and antimicrobial activity. The structures were confirmed by their 1H NMR, 13C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive strains, Gram-negative strains, and fungi. Results: Among the synthesized compounds, compound 12h showed the highest activity (IC50 = 0.416 μM) against ALK5 kinase. Compound 12h exhibited a good selectivity index of > 24 against p38α MAP kinase and was 6.0-fold more selective than the clinical candidate, compound 2 (LY-2157299). Nearly all the compounds displayed high selectivity toward both Gram-positive and Gram-negative bacteria. They also showed similar or 2.0-fold greater antifungal activity (minimum inhibitory concentration [MIC] = 0.5 µg/mL) compared with the positive control compounds Gatifloxacin (MIC = 0.5 µg/mL) and fluconazole (MIC = 1 µg/mL). Conclusion: The findings suggest that the synthesized rhodanine compounds have good ALK5 inhibitory activity and can be used for further research and development as potential antifungal drugs.

Modelling flexible protein–ligand binding in p38α MAP kinase using the QUBE force field

The accuracy of quantum mechanical bespoke (QUBE) force fields for protein–ligand binding free energy calculations are benchmarked against experiment.

Conformational selection vs. induced fit: insights into the binding mechanisms of p38α MAP Kinase inhibitors

Multilateration using EPR distance restraints shows direct evidence of both induced-fit and conformational selection mechanisms of p38α depending on the ligand type.

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>