Despite the enormous advancements in method development, reliable prediction of the binding modes and affinities of P-L complexes still remains an unsolved task . Quantum mechanics (QM) is the most accurate technique for modeling chemical structures, but accurate ab initio QM calculations are practically limited to small systems due to the complexity and time inefficiency of the method . Semiempirical Quantum Mechanics (SQM), while based on QM, adopts systematic approximations and utilizes empirical parameters fitted to reference data. This has led to computational schemes that are faster than ab initio calculations by several orders of magnitude, albeit less accurate . SQM-based approaches have emerged as an efficient computational method for systems up to thousands of atoms , and have shown reasonably good performance on representative drug-protein systems . The majority of the employed SQM methods are combined SQM/Molecular Mechanics (SQM/MM) approaches: the ligand or the ligand and some protein residues are considered flexible and therefore treated at an SQM level, whereas the rest of the protein at an MM level .