Application of Semiempirical Quantum Mechanical Methods To Accurately Estimate Ligand-Binding Structure in Biological Systems: Protein Kinase Case Study

This study presents a quantum mechanical (QM)-based workflow utilizing semiempirical methods for estimating ligand binding poses in protein-ligand complexes, focusing on kinases of pharmaceutical relevance: CDK2, CK2, p38α, and CAMK1DA. The protocol integrates xTB-based docking with PM6-D3H4X rescoring within a QM/MM framework, aiming to enhance the structural accuracy over traditional docking methods. Drug-like and fragment-like ligands were tested across different receptor structures to assess robustness for CDK2 and CK2. Results show that for drug-like ligands the QM approach reproduces experimental poses. However, performance is less consistent for the fragment-like ligands we have considered, perhaps due to structural ambiguity and weak binding interactions limiting accuracy.