Accurate Enthalpies\nof Formation for Bioactive Compounds\nfrom High-Level Ab Initio Calculations with Detailed Conformational\nTreatment: A Case of Cannabinoids

Our\nrecently developed approach based on the local coupled-cluster\nwith single, double, and perturbative triple excitation [LCCSD(T)]\nmodel gives very efficient means to compute the ideal-gas enthalpies\nof formation. The expanded uncertainty (95% confidence) of the method\nis about 3 kJ·mol<sup>–1</sup> for medium-sized compounds,\ncomparable to typical experimental measurements. Larger compounds\nof interest often exhibit many conformations that can significantly\ndiffer in intramolecular interactions. Although the present capabilities\nallow processing even a few hundred distinct conformer structures\nfor a given compound, many systems of interest exhibit numbers well\nin excess of 1000. In this study, we investigate how to reduce the\nnumber of expensive LCCSD(T) calculations for large conformer ensembles\nwhile controlling the error of the approximation. The best strategy\nfound was to correct the results of the lower-level, surrogate model\n(density functional theory, DFT) in a systematic manner. It was also\nfound that the error in the conformational contribution introduced\nby a surrogate model is mainly driven by a systematic (bias) rather\nthan a random component of the DFT energy deviation from the LCCSD(T)\ntarget. This distinction is usually overlooked in DFT benchmarking\nstudies. As a result of this work, the enthalpies of formation for\n20 cannabinoid and cannabinoid-related compounds were obtained. Comprehensive\nuncertainty analysis suggests that the expanded uncertainties of the\nobtained values are below 4 kJ·mol<sup>–1</sup>.