Abstract
The Quantitative Structure Activity Relationship (QSAR) study is performed over a set of 15, 4-alkyl/aryl-substituted 1- [benzofuran-2-yl-phenylmethyl]-1 H-triazoles derivatives. This study is based on the application of physicochemical parameters in QSAR. The parameters include (MR (molar refractivity), MW (molecular weight), Pc (parachor), St (surface tension), D (density), Ir (index of refraction) and log P (partition coefficient). The parameters describing physiochemical properties are used as independent variables and the biological activity (IC(50)) is considered as dependent variable in multiple regression analysis. Different models were generated with high co-efficient of determination (R(2)). The 2D-QSAR study identified compounds capable of inhibiting the metabolic breakdown of the retinoid (trans-retinoic acid (ATRA)) involved in the activation of specific nuclear Retinoic acid receptors (RARs). This study identifies R115866 as a potential inhibitor of the cytochrome P450 (CYP) mediated metabolism with increased RA levels for retinoid actions.
Highlights
In human, CYP26A1 mapped to chromosomes 10q23-q24 is expressed in the liver, heart, pituitary gland, adrenal gland, testis, brain and placenta
We identified compounds capable of inhibiting the metabolic breakdown of the retinoid because high rate metabolism largely impairs the biological efficiency of RA
Quantitative Structure Activity Relationship (QSAR) was performed on a series of 15, 4-alkyl/aryl-substituted 1-[benzofuran-2-yl-phenylmethyl]-1 H-triazoles derivatives with the physicochemical parameters (Table 3, see supplementary material), the biological activity is a measure of inhibitory activity indicators (Table 1, see supplementary material)
Summary
CYP26A1 mapped to chromosomes 10q23-q24 is expressed in the liver, heart, pituitary gland, adrenal gland, testis, brain and placenta. The enzyme is an important regulator of differentiation and a possible modulator of disease states in indirectly controlling ATRA and other retinoid concentrations. Other CYPs are induced by ATRA, it is thought that CYP26A1 is likely to be the most important enzyme involved in its degradation [1]. ATRA regulates epithelial differentiation and growth through activation of specific nuclear retinoic acid receptors (RARs). QSAR represents an attempt to correlate structural or property descriptors of compound with activities. These physiochemical descriptors include parameters to account for hydrophobicity, topology, electronic parameters and steric effects. These are determined empirically by computational methods. Quantitative Structure Activity Relationship (QSAR) is currently being applied in many disciplines pertaining to drug design and environmental risk assessments [2]
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