title: Cellular quantitative structure-activity relationship (Cell-QSAR): conceptual dissection of receptor binding and intracellular disposition in antifilarial activities of Selwood antimycins.
abstract: We present the cellular quantitative structure-activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug's lipophilicity, acidity, and other properties. We conceptually combined the DF with our multispecies, multimode version of the frequently used ligand-based comparative molecular field analysis (CoMFA) method, forming a single correlation function for fitting the cell-level activities. The resulting cell-QSAR model was applied to the Selwood data on filaricidal activities of antimycin analogues. Their molecules are flexible, ionize under physiologic conditions, form different intramolecular H-bonds for neutral and ionized species, and cross several membranes to reach unknown receptors. The calibrated cell-QSAR model is significantly more predictive than other models lacking the disposition part and provides valuable structure optimization clues by factorizing the cell-level activity of each compound into the contributions of the receptor binding and disposition.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Vermont Campus, Colchester, Vermont 05446, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Natesan
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Viera
authors.initials: V
authors.lastname: Lukacova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bartus
authors.forename: Akash
authors.initials: A
authors.lastname: Khandelwal
authors.forename: Rajesh
authors.initials: R
authors.lastname: Subramaniam
authors.forename: Stefan
authors.initials: S
authors.lastname: Balaz
mesh_terms: D000968:Antimycin A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D015195:Drug Design; D005369:Filaricides / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D005369:Filaricides; D008024:Ligands; C032456:antimycin; D000968:Antimycin A