Integrative Computational Design of PD-L1 Inhibitors, Utilizing MD Simulations and DFT Studies to Guide Cancer Treatment through Atomic and Electronic Properties

The emphasis on immunological checkpoints, including Programmed Death-Ligand1 (PD-L1), is considered a critical strategy for enhancing cancer treatment in global cancer research. PD-L1 plays a pivotal role in enabling cancer cells to evade the immune system, thereby representing a primary target for cancer immunotherapy. Therefore, this study employs in silico methods to identify the small molecule inhibitors against PD-L1 protein. A machine-learning-based QSAR model was used to screen 412,903 natural compounds conjugated with Lipinski’s drug-likeness properties and toxicity evaluations. The Gradient Boosting Regressor was selected for the screening, which had the highest correlation of [Formula: see text] value (0.709) and lowest MSE (0.321) with the experimental binding, indicating its accurate binding affinity predictions. Screened compounds proceeded under additional evaluation using molecular docking and Density Functional Theory (DFT), resulting in the identification of the two most potential binders. Moreover, the study employed Molecular Dynamics (MDs) simulations and binding free energy calculations (MM/GBSA) to evaluate the compounds’ ability to bind with PD-L1, potentially impeding its interaction with PD-1. Based on the results, it was observed that compound-2 consistently and reliably interacts with PD-L1. In order to assess the robustness and stability of the protein-ligand complex of compound-2 and PD-L1, the simulations were executed in triplicates, each lasting 100 ns. Compound-2 showed sufficient hydrogen bonding with functional residues of the protein, including Asp122(A), Tyr56(B) and Tyr56(A), which are crucial for the stability and inhibition of PD-L1. Additionally, compound-2 obtained the most favorable binding free energy (−13.74 kcal/mol). Overall, the study suggested that compound 2 has the ability to hinder the interaction between PD-L1 and PD-1, hence enhancing the immune response against cancer cells. Additional experimental studies into the application of compound 2 in cancer immunotherapy could yield supportive results.