Virtual screening of 4-anilinoquinazoline analogues as EGFR kinase inhibitors: importance of hydrogen bonds in the evaluation of poses and scoring functions

Abstract

Virtual Screening (VS) is a computational technique that allows selection and ranking of possible hits from a library of compounds. We have carried out VS on 128 selected EGFR kinase inhibitors with GOLD and LigandFit. From the experimental crystal structure of the erlotinib-EGFR complex, three key hydrogen bonds were identified as responsible for anchoring the ligand in the active site. These are of the N-H···N, O_w-H···N, and C-H···O types. Failure to include the hydrogen-bonded water molecule that forms the O_w-H···N bond leads to incorrect results. Of the three interactions, the C-H···O formed by an activated C-H group is the best conserved. On the basis of the efficacy of these hydrogen bonds, the poses were classified into one of three categories: close, shifted, and misoriented. In the VS context, all three interactions need to be modeled correctly so that correct poses and affinities are obtained, and this happens in ligands of the close variety. Cross scoring wherein the poses from one software are input into another for scoring and consensus scoring wherein the scores from various software packages are weighted are also helpful in obtaining better agreements.