LAUSR

Abstract This study examines the interaction of 137 antimalarial and antihuman African trypanosomiasis compounds [bis(2-aminoimidazolines), bisguanidinediphenyls and polyamines] on three different in vitro assays ( Trypanosoma brucei rhodesiense ( T . b . r .), Plasmodium falciparum ( P . f .) and cytotoxicity-L6 cells). Δ T m values, wherever available, were also examined for the considered ligands. Eight DNA–ligand complexes and one DNA structure without ligand were selected from protein data bank (PDB) based on the structural similarity. Geometry optimization of all the considered ligands was carried out at the B3LYP/6-31G(d) level of theory. The AutoDock4 tool was utilized for the docking of these molecules at the minor groove of nine selected DNA crystal structures. We observed DT20, DA6, DT8 and DT19 residues generally interact with most of the considered ligands. Molecular dynamics simulations, molecular mechanics–generalized born surface area and molecular mechanics–Poisson Boltzmann surface area calculations indicate that the docked poses are generally stable and docked ligands do not show much deviation in the minor groove of DNA until 10 ns simulation. Efficient and statistically significant quantitative structure–activity relationship models for T . b . r ., P . f ., C-L6 and Δ T m values were developed. All the generated models are internally and externally validated. We predicted a few ligands with significant IC 50 values against P . f . based on the developed models. These results may help to design new and potent antimalarial and antihuman African trypanosomal compounds. Graphic abstract