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

Abstract

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 r = 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.

Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors

“…After the MD simulations, the most stable sub-trajectories of the five ALK-5-inhibitor structures were selected (20 ns for each complex) for binding free energy calculations using the SIE method. These results are presented in Table 1 along with the ∆G value for the benchmark compound (4-( [1,2,4]triazolo [1,5-a]pyridin-6-yl)-N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1carbothioamide), which is a known ALK-5 inhibitor (IC 50 = 0.57 nM) [53]. The binding free energies were calculated and compared with the values obtained from the docking simulations, as reported in Table 1.…”

An electronic point of view on the inhibition of ALK-5 by bioactive candidates related to cancer

“…The initial conformation of each ligand-receptor complex, used in the QM/MM (quantum mechanics/molecular mechanics, using the ONIOM method) calculations, was previously obtained [8], and, for these calculations, we employed Gaussian09 [33]. Initially, the binding site of ALK-5 was delimited at a radius of 5 Å, and this cut was done by using Pymol [34].…”

“…Several studies have shown that the ALK-5 inhibition is related to various types of tumors, such as pancreatic, breast and colon, and these studies have been done to induce the inhibition of TGF-β signaling [7][8][9]. In this paper, six molecules ((1 (4-( [1,2,4] triazole [1,5-a] Escola de Artes, Universidade de São Paulo Ciências e Humanidades, Av.…”

Studies on the Dual Activity of EGFR and HER-2 Inhibitors Using Structure-Based Drug Design Techniques

“…Several studies attempt to inhibit the biological targets under study and one way to study the interaction processes between HER-2/EGFR and inhibitor molecules is employing molecular modeling methods, which are often employed in medicinal chemistry [6,13,14,15,16]. Using these techniques, it is possible to identify the interactions that occur between bioactive molecules and biological receptors.…”