Computational analyses of interactions between ALK-5 and bioactive ligands: insights for the design of potential anticancer agents

<p>Activin Receptor-Like Kinase 5 (ALK-5) is related to some types of cancer, such as breast, lung, and pancreas. In this study, we have used molecular docking, molecular dynamics simulations, and free energy calculations in order to explore key interactions between ALK-5 and six bioactive ligands with different ranges of biological activity. The motivation of this work is the lack of crystal structure for inhibitor–protein complexes for this set of ligands. The understanding of the molecular structure and the protein–ligand interaction could give support for the development of new drugs against cancer. The results show that the calculated binding free energy using MM-GBSA, MM-PBSA, and SIE is correlated with experimental data with <i>r</i>² = 0.88, 0.80, and 0.94, respectively, which indicates that the calculated binding free energy is in excellent agreement with experimental data. In addition, the results demonstrate that H bonds with Lys232, Glu245, Tyr249, His283, Asp351, and one structural water molecule play an important role for the inhibition of ALK-5. Overall, we discussed the main interactions between ALK-5 and six inhibitors that may be used as starting points for designing new molecules to the treatment of cancer.</p

A comparative modeling and molecular docking study on <i>Mycobacterium tuberculosis</i> targets involved in peptidoglycan biosynthesis

<p>An alarming rise of multidrug-resistant <i>Mycobacterium tuberculosis</i> strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in <i>M. tuberculosis</i> are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 <i>M. tuberculosis</i> strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected <i>M. tuberculosis</i> targets involved in peptidoglycan biosynthesis.</p