title: Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.
abstract: Quantum mechanical semiempirical comparative binding energy analysis calculations have been carried out for a series of protein kinase B (PKB) inhibitors derived from fragment- and structure-based drug design. These protein-ligand complexes were selected because they represent a consistent set of experimental data that includes both crystal structures and affinities. Seven scoring functions were evaluated based on both the PM3 and the AM1 Hamiltonians. The optimal models obtained by partial least-squares analysis of the aligned poses are predictive as measured by a number of standard statistical criteria and by validation with an external data set. An algorithm has been developed that provides residue-based contributions to the overall binding affinity. These residue-based binding contributions can be plotted in heat maps so as to highlight the most important residues for ligand binding. In the case of these PKB inhibitors, the maps show that Met166, Thr97, Gly43, Glu114, Ala116, and Val50, among other residues, play an important role in determining binding affinity. The interaction energy map makes it easy to identify the residues that have the largest absolute effect on ligand binding. The structure-activity relationship (SAR) map highlights residues that are most critical to discriminating between more and less potent ligands. Taken together the interaction energy and the SAR maps provide useful insights into drug design that would be difficult to garner in any other way.
authors.affiliation: QuantumBio Inc, 200 Innovation Boulevard, State College, Pennsylvania 16803 and Johnson & Johnson Pharmaceutical Research and Development, LLC, Welsh and McKean Roads, PO Box 776, Spring House, Pennsylvania 19477, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.forename: Alan C
authors.initials: AC
authors.lastname: Gibbs
authors.forename: Charles H
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Martin B
authors.initials: MB
authors.lastname: Peters
authors.forename: Lance M
authors.initials: LM
authors.lastname: Westerhoff
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt