Quantum Mechanical-Based Stability Evaluation of Crystal Structures for HIV-Targeted Drug Cabotegravir

The long-acting parenteral formulation of the HIV integrase inhibitor cabotegravir (GSK744) is currently being developed to prevent HIV infections, benefiting from infrequent dosing and high efficacy. The crystal structure can affect the bioavailability and efficacy of cabotegravir. However, the stability determination of crystal structures of GSK744 have remained a challenge. Here, we introduced an ab initio protocol to determine the stability of the crystal structures of pharmaceutical molecules, which were obtained from crystal structure prediction process starting from the molecular diagram. Using GSK744 as a case study, the ab initio predicted that Gibbs free energy provides reliable further refinement of the predicted crystal structures and presents its capability for becoming a crystal stability determination approach in the future. The proposed work can assist in the comprehensive screening of pharmaceutical design and can provide structural predictions and stability evaluation for pharmaceutical crystals.