Elucidating the Efficacy of Clinical Drugs Using FMO

It is known that first-principles based fragment molecular orbital (FMO) theory can be used to study protein–ligand interactions quantitatively. This includes obtaining amino acid residue-wise interactions with the ligand and detailed interaction components such as electrostatic, dispersion, charge-transfer, and exchange-repulsion. This chapter discusses the ability of FMO calculations on elucidating the efficacy of the clinical drugs that are available in the market. For this purpose, two kinds of clinical drugs, dipeptidyl peptidase IV (DPP-4) inhibitors (sitagliptin, linagliptin, alogliptin, teneligliptin, omarigliptin, and trelagliptin) and peroxisome proliferator-activated receptor-α (PPARα) modulators (fenofibrate and pemafibrate), were considered. The FMO calculations on relevant protein-drug complexes were made at the correlated Resolution-of-Identify second-order Moller Plesset (RI-MP2) level of theory utilizing correlation consistent double-zeta (cc-pVDZ) basis set. The results discussed here clearly reveal that interfragment interaction energies obtained using FMO calculations correlate significantly with the activity of the drugs and hence the activity of the drugs can be positively identified through FMO calculations. The results presented here further encourages that this novel calculation approach can be used for other types of drugs too to study the efficacy of the clinical as well as potential drugs.