QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis Prodrugs
| Autor: | C. A. Brandt, Elizabeth Igne Ferreira, Veni Maria Andres Felli, Kerly Fernanda Mesquita Pasqualoto, João Paulo S. Fernandes |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Molecular model Stereochemistry medicine.drug_class Antitubercular Agents Quantitative Structure-Activity Relationship Pharmaceutical Science Microbial Sensitivity Tests Antimycobacterial Mycobacterium tuberculosis chemistry.chemical_compound Pyrazinoic acid Drug Discovery Partial least squares regression medicine Prodrugs Least-Squares Analysis biology Esters Pyrazinamide Prodrug biology.organism_classification chemistry Drug Design Algorithms medicine.drug |
| Zdroj: | Archiv der Pharmazie. |
| ISSN: | 1521-4184 0365-6233 |
| DOI: | 10.1002/ardp.200900216 |
| Popis: | Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents. |
| Databáze: | OpenAIRE |
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