title: Towards an integrated description of hydrogen bonding and dehydration: decreasing false positives in virtual screening with the HYDE scoring function.
abstract: We developed a new empirical scoring function, HYDE, for the evaluation of protein-ligand complexes. HYDE estimates binding free energy based on two terms for dehydration and hydrogen bonding only. The essential feature of this scoring function is the integrated use of log P-derived atomic increments for the prediction of free dehydration energy and hydrogen bonding energy. Taking the dehydration of atoms within the interface into account shows that some atoms contribute favorably to the overall score, while others contribute unfavorably. For instance, hydrogen bond functions are penalized if they are dehydrated unless they can overcompensate this loss by forming a hydrogen bond with excellent geometry. The main stabilizing contribution represents the removal of apolar groups from the water: the hydrophobic effect. Initial studies using the DUD dataset show that with HYDE, there is a significant decrease in false positives, a reasonable categorization of compounds as either non-binders, weak, medium or strong binders, and in particular, there is a generally applicable and thermodynamically sensible cutoff score below which there is a high likelihood that the compound is indeed a binder.
authors.affiliation: Center for Bioinformatics, University of Hamburg, Bundesstrasse 43, 20146 Hamburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Reulecke
authors.forename: Gudrun
authors.initials: G
authors.lastname: Lange
authors.forename: Jürgen
authors.initials: J
authors.lastname: Albrecht
authors.forename: Robert
authors.initials: R
authors.lastname: Klein
authors.forename: Matthias
authors.initials: M
authors.lastname: Rarey
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D003890:Desiccation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry* / Q000187:drug effects; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D009930:Organic Chemicals; D011506:Proteins; D014867:Water