QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis Prodrugs
Arch. pharm
; 343(2): 91-97, Jan 22, 2010.
Article
in English
| Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP, SESSP-IBACERVO
| ID: biblio-1059804
Responsible library:
BR78.1
Localization: BR78.1
ABSTRACT
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, r2 = 0.68, q2 = 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.
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Collection:
National databases
/
Brazil
Health context:
Neglected Diseases
Health problem:
Neglected Diseases
/
Tuberculosis
Database:
Sec. Est. Saúde SP
/
SESSP-IBACERVO
/
SESSP-IBPROD
Main subject:
Pyrazinamide
/
Models, Molecular
/
Mycobacterium tuberculosis
/
Antitubercular Agents
Type of study:
Prognostic study
Language:
English
Journal:
Arch. pharm
Year:
2010
Document type:
Article
Institution/Affiliation country:
Instituto Butantan/BR