Abstract <p>To delve deeper into the complexation phenomenon of the antipsychotic drug Olanzapine (OLP) with CRYSMEB, we employed two independents computational strategies: a systematic stepwise quantum chemical docking approach and Monte Carlo (MC) simulations. Density Functional Theory (DFT) and its dispersion-corrected variants, namely B3LYP, CAM-B3LYP, B3LYP-D2 and B3LYP-D3 functionals were used with the 6-31G(d) basis set to refine the most stable docked conformations obtained from stepwise docking procedure. All methods supported the partial inclusion of OLP within CRYSMEB cavity, with a significant distortion of the drug molecule. The phenyl moiety is entirely buried inside the host cavity, while the diazepine ring is partially to fully extruded depending on the functional. In contrast, both piperazine and thiophene rings are expelled on the primary rim side. The experimental validation of this binding mode suppports the reliability of the systematic stepwise approach. Frontier Molecular Orbital analysis and global reactivity descriptors, revealed significant charge transfer within the complex. Interaction patterns were further characterized using Natural Bond Orbital (NBO), Quantum Theory of Atoms in Molecules (QTAIM), Non-Covalent Interaction-Reduced Density Gradient (NCI-RDG) and Independent Gradient Model (IGM) analyses which consistently identified weak to moderate H-bonds along with dominant VdW interactions. Energy Decomposition Analysis (EDA) confirmed the prevalence of electrostatic and dispersion forces to the overall complex stability. These weak non-covalent interactions are crucial for enabling drug delivery and release at the targeted site. Finally, a strong correlation was observed between topological parameters, interaction energies, and the intermolecular H-bond distances, with B3LYP-D3 providing the most consistent description.</p> Graphical abstract <p></p>