Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation.

The BCL-XL protein is among the most important members of the anti-apoptotic subfamily of the BCL-2 protein family, and is currently a promising new target for anti-tumor drug research. However, the BCL-XL/2 proteins have similar structures and functions, which could lead to undesirable side effects because of inhibitors that can bind to both BCL-XL and BCL-2. Therefore, it is crucial to expound on the structural basis of the selective mechanism towards BCL-XL/2 inhibition. In the current study, we employed hybrid computational methods including molecular docking and dynamics simulation, MM/GBSA energy calculation, alanine scanning mutagenesis and Hirshfeld surface analysis to comprehensively reveal the selectivity mechanism towards BCL-XL/2 from multiple perspectives, revealing the significant effects of the BCL-XL residues SER106 and LEU108 as well as the BCL-2 residue ASP103 on the inhibitory selectivity. Overall, our findings provide useful references for the rational design of BCL-XL/2 selective inhibitors with better affinity.

Identification of raloxifene as a novel α-glucosidase inhibitor using a systematic drug repurposing approach in combination with cross molecular docking-based virtual screening and experimental verification.

α-Glucosidase is a promising target for the treatment of diabetes. Drug repurposing can increase the chances of discovering an active inhibitor. Therefore, this study aimed to identify potential α-glucosidase inhibitor using drug repurposing and in silico strategies. We identified critical amino acid residues of the three α-glucosidase proteins. Based on cross molecular docking studies of three α-glucosidase proteins and drugs in the FDA database, we screened hits with the favorable binding affinities and modes targeting the three proteins. Subsequently, an in vitro activity assay showed that raloxifene was an excellent inhibitor of α-glucosidase. Moreover, molecular dynamics simulations of raloxifene and three proteins were performed to assess the stability of the protein-hit systems in physiological conditions and clarify protein-hit interactions. We also performed the binding free energy calculation, Hirshfeld surface and alanine scanning mutagenesis analyses. These results demonstrated that binding between raloxifene and the three proteins was stable, and the critical amino acid residues of the three proteins formed stable contacts with raloxifene. The molecular mechanisms agree well with its activity, reinforcing that raloxifene is a candidate α-glucosidase inhibitor. Our study smoothes the path for the development of novel a-glucosidase inhibitors with high efficacy and low toxicity for the treatment of diabetes.