Human protein tyrosine phosphatase 1B inhibitors: QSAR by genetic function approximation

Abstract

Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. As a result there is a growing interest in the development of potent and specific inhibitors for this enzyme. This quantitative structure-activity relationship (QSAR) study for a series of formylchromone derivatives as PTP 1B inhibitors was performed using genetic function approximation (GFA) technique. The QSAR models were developed using a training set of 29 compounds and the predictive ability of the QSAR model was evaluated against a test set of 7 compounds. The internal and external consistency of the final QSAR model was 0.766 and 0.785. The statistical quality of QSAR models was assessed by statistical parameters r², (crossvalidated r²), (predictive r²) and lack of fit (LOF) measure. The results indicate that PTP 1B inhibitory activity of the formylchromone derivatives is strongly dependent on electronic, thermodynamic and shape related parameters.

Keywords::

• Quantitative structure-activity relationship (QSAR)
• genetic function approximation (GFA)
• protein tyrosine phosphatase 1B (PTP 1B)
• non-insulin dependent diabetes mellitus (NIDDM)
• descriptor
• inhibition

Acknowledgements

The authors thank the University Grants Commission, New Delhi for the DRS Project.