Thermochemical and Quantum Descriptor Calculations for Gaining Insight into Ricin Toxin A (RTA) Inhibitors

[Image: see text] In this work, we performed a study to assess the interactions between the ricin toxin A (RTA) subunit of ricin and some of its inhibitors using modern semiempirical quantum chemistry and ONIOM quantum mechanics/molecular mechanics (QM/MM) methods. Two approaches were followed (calculation of binding enthalpies, ΔH(bind), and reactivity quantum chemical descriptors) and compared with the respective half-maximal inhibitory concentration (IC(50)) experimental data, to gain insight into RTA inhibitors and verify which quantum chemical method would better describe RTA–ligand interactions. The geometries for all RTA–ligand complexes were obtained after running classical molecular dynamics simulations in aqueous media. We found that single-point energy calculations of ΔH(bind) with the PM6-DH+, PM6-D3H4, and PM7 semiempirical methods and ONIOM QM/MM presented a good correlation with the IC(50) data. We also observed, however, that the correlation decreased significantly when we calculated ΔH(bind) after full-atom geometry optimization with all semiempirical methods. Based on the results from reactivity descriptors calculations for the cases studied, we noted that both types of interactions, molecular overlap and electrostatic interactions, play significant roles in the overall affinity of these ligands for the RTA binding pocket.