title: Surface descriptors for protein-ligand affinity prediction.
abstract: Molecular descriptors calculated by the VolSurf program have been extensively used to model pharmacokinetic properties, e.g., passive permeability through the gastrointestinal tract or through the blood-brain barrier. These descriptors quantify steric, hydrophobic, and hydrogen bond interactions between model compounds and different environments. Since these interactions are the same as those involved in the ligand-receptor binding, VolSurf descriptors could potentially be relevant in modeling this process as well. We obtained a significant model (r(2) = 0.85, q(2) = 0.75) using VolSurf descriptors derived from the ligand, the protein, and the ligand-protein complex for a diverse set of 38 structures previously used in the VALIDATE (ref 23) training set. Furthermore, a statistically significant model (r(2) = 0.94, q(2) = 0.89) was obtained using the same type of descriptors for a homogeneous set of glycogen phosphorylase inhibitors (ref 25). Using the VolSurf computational framework, both ligand-receptor binding and the ligand's pharmacokinetic behavior can be modeled simultaneously during the preclinical aspects of drug discovery.
authors.affiliation: DMPK & Bioanalytical Chemistry, AstraZeneca R & D Mölndal, S-431 83 Mölndal, Sweden. ismael.zamora@telefonica.net
authors.forename: Ismael
authors.initials: I
authors.lastname: Zamora
authors.forename: Tudor
authors.initials: T
authors.lastname: Oprea
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ungell
mesh_terms: D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D010599:Pharmacokinetics; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008024:Ligands; D011506:Proteins