Understanding allosteric modulation in PPARγ receptors by comparative QSAR analysis
By Ram Babu Tripathi, Manish Sharma, Amrish Chandra, Arun Arya, Abhishek Srivastva, Vijay Kumar
Quantitative structure activity relationship (QSAR) analysis was carried out on different series of 2-alkoxydihydrocinnamates(eq.1), azaindole-α-alkyloxyphenyl propionic acids(eq.2), combined series of oxime ethers of α-acyl-β-henylpropanoic acids(I) and N-(2-Benzoylphenyl)-L-tyrosine derivatives(II) (eq.3) as PPARγ agonists. A range of electronic, steric and lipophilic parameters were tried. These results indicate the importance of Vw (van der Waals radius) and CMR. The combined model of (I) and (II) was found to be of interest in deriving new analogues with better activity as it indicated a positive parabolic relationship of biological activity (EC50) with CMR (eq3).
-logEC50(M)=2.053(0.899)R1Vw-1.921(0.625)R 2Vw+6.476(0.375) r=0.950,R2=0.900,Q2=0.800,s= 0.177,CMRrange=11.04-13.59 (1)
-logEC50(M)=-0.953(0.472)RVw+0.847(0.344)I1+0.495(0.249)I2+6.476(0.379) r=0.935,R2=0.875,Q2=0.785,s=0.186,CMRrange= 9.72- 12.4 (2)
-logEC50(M)=8.404(2.509)CMR-0.293(0.089)CMR2-1.757(0.475)In-50.286(17.487) r=0.917,R2=0.841,Q2=0.754,s=0.380,CMRrange=14.2-17.03,CMRoptim=14.3 (3)
Where In=1, for the presence of NH fragments in the subsitutents. New substituents were proposed in (I) which bring the CMR value of the molecules in the optimum range. It is tempting to speculate that the binding mechanism of (I) with PPARγ is different than 2-alkoxydihydrocinnamates and azaindole-α-alkyloxyphenylpropionic acids as the relationship of CMR (range:9-14.3) of (I) with activity is opposite to cinnamates and phenylpropionic acids. The downward slope of CMR in eq.(3) and modified forms(models with parameter CMR) of equation (1) and (2) were similar(0.293,0.247 and 0.329) which laterally authenticates the credibility of the proposed models.
Keywords : QSAR, PPARγ, CMR, Type-2 Diabetes.