Author(s)

Julie B. Ealy^*, Noorhaan Abouomar, Justin Cogan, Paolo Flauta, Liliana Nassar, Matthew Mekolochik, Sarah Ramzy, Christopher Shannon, Habib Yazgi

Penn State Lehigh Valley, Center Valley, PA, USA.

Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.

Lipinski’s “Rule of Five”, Drug-Like and Nondrug-Like Molecules, HIV-1 Integrase, Estimated Binding Energy, Pharmacophore

Ealy, J. , Abouomar, N. , Cogan, J. , Flauta, P. , Nassar, L. , Mekolochik, M. , Ramzy, S. , Shannon, C. and Yazgi, H. (2017) Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H. Advances in Bioscience and Biotechnology, 8, 163-183. doi: 10.4236/abb.2017.85013.