Benchmarking of Semiempirical Quantum-Mechanical Methods on Systems Relevant to Computer-Aided Drug Design

The semiempirical
quantum mechanical (SQM) methods used in drug
design are commonly parametrized and tested on data sets of systems
that may not be representative models for drug–biomolecule
interactions in terms of both size and chemical composition. This
is addressed here with a new benchmark data set, PLF547, derived from protein–ligand
complexes, consisting of complexes of ligands with protein fragments
(such as amino-acid side chains), with interaction energies based
on MP2-F12 and DLPNO-CCSD­(T) calculations. From these, composite benchmark
interaction energies are also built for complexes of the ligand with
the complete active site of the protein (PLA15 data set). These data
sets are used to test multiple SQM methods with corrections for noncovalent
interactions; the role of the solvation model in the calculations
is tested as well.