Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins
| Autor: | Vladimir Bartus, Rajesh Subramaniam, Tiansheng Wang, Senthil Natesan, Stefan Balaz, Viera Lukacova, Akash Khandelwal |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Chemical Phenomena Antimycin A Quantitative Structure-Activity Relationship Ligands 010402 general chemistry 01 natural sciences Article 03 medical and health sciences Drug Discovery Receptor 030304 developmental biology 0303 health sciences Chemistry Hydrogen Bonding Disposition Ligand (biochemistry) 0104 chemical sciences Filaricides Membrane Biochemistry Drug Design Lipophilicity Molecular Medicine Function (biology) Intracellular Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm201371y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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