Exploration of Virtually Designed and Developed Thiadiazole Derivatives as ULK1/2 Inhibitors: In silico Approach

Abstract

Cancer is a group of diseases distinguished by uncontrollable cell division. The underlying causes are complex and include multiple genes and pathways. Many targeted therapies are effective in treating cancer. In Current research, we were using the autophagy pathway of cell death. Here, we are exploring some thiadiazole derivatives that are specific to ULK inhibition, and for a better understanding of ligand and target we have assessed all the molecules by using some computational approaches. The current study focuses on the In-silico evaluation and molecular prediction of some thiadiazole derivatives as ULK (Human Autophagy Initiating Kinase) inhibitors. Some thiadiazole derivatives were subjected to In-silico evaluation involving Molecular docking, Pharmacophore modelling, PASS prediction and Molecular dynamic simulation (MD) along with PCA analysis. In addition, drug-likeness was determined using the Lipinski rule of five. Among all proposed thiadiazole derivatives, we found a few ligands such as 2d, 4e, and 4d with the lowest binding energy score (-11.3 kcal/mol, -11.2 kcal/mol and -11.0 kcal/mol), respectively. Drug-likeness properties include an excellent lipophilic character with good permeability (1.97, 2.86, and 2.73) observed with the above derivatives. In addition, better binding specificity (94.79, 94.70, and 74.57) and better enzyme potential inhibitory activity (0.04, 0.00, 0.14) were noticed with ULK receptors in comparison to STD (Standard) molecules. Using pharmacophore modelling, we identified potential chemical features of the designed compounds. Moreover, molecular dynamics and PCA analysis of compound 4d showed stable conformation with 4WNP. Compared to STD compounds, with no violation, the bioactivity and likeness score of ligands 2d, 4e, and 4d were relatively high, indicating that they were excellent ULK inhibitors. These ligands also had the lowest binding score, which may aid in determining the stability of ligands. Pharmacophore modeling data suggested the essential chemical features of designed compounds required for the activity. The MD simulation and PCA study confirmed the stability of the 4d complex with 4WNP. These parameters allow consideration of the most promising candidates to be synthesized.