Rational Cocrystal Design of Hesperetin Using Integrated Molecular Docking, SAPT, and DFT Approach

Cocrystallization represents a promising strategy for enhancing the physicochemical properties of poorly soluble active pharmaceutical ingredients (APIs), such as hesperetin (HES), a bioflavonoid with significant therapeutic potential but limited aqueous solubility. Predicting suitable coformers for stable cocrystal formation with a given API remains challenging, as conventional experimental screening is resource-intensive and largely dependent on trial-and-error. This study aims to predict the cocrystal-forming potential of hesperetin with various coformers through an integrated in silico approach. Three computational methods were utilized i.e. molecular docking for preliminary screening of coformers based on binding affinity and hydrogen-bonding capacity; Symmetry-Adapted Perturbation Theory (SAPT) to analyze intermolecular interaction energies and assess contributions from electrostatics, induction, dispersion, and exchange-repulsion; and Density Functional Theory (DFT) to optimize the geometry of hesperetin–coformer complexes and calculate interaction energies indicative of cocrystal stability. The findings indicate that adipic acid and glutaric acid are the most promising coformers, exhibiting strong interaction energy (ΔEint) of-31.4 kcal/mol, directional hydrogen bonding, and favorable secondary noncovalent interactions. Although citric acid can form hydrogen bonds, it provides lower net stabilization due to steric hindrance. In summary, this computational framework offers a rational and efficient strategy for identifying suitable coformers prior to laboratory synthesis. This approach may accelerate the development of solubility-enhanced hesperetin formulations and is broadly applicable to other poorly soluble naturally occurring compounds.