Quantitative Structure–Activity Relationship and Quantitative Structure–Pharmacokinetics Relationship of 1,4-Dihydropyridines and Pyridines as Multidrug Resistance Modulators
The aim of this study was to develop quantitative structure–activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors.
Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca2+ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the “leave-one-out” method was performed to evaluate the predictive performance of models.
For Ca2+ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R2 = 0.90), and cross-validation confirmed the predictive ability of the model (Q2 = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69).
QSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca2+ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.
Key Wordsdihydropyridines (DHPs) multidrug resistance (MDR) P-glycoprotein (P-gp) quantitative structure–activity relationship (QSAR) quantitative structure–pharmacokinetic relationship (QSPKR)
Connolly surface area
Connolly surface volume
heat of formation
energy of the highest occupied molecular orbital
energy of the lowest unoccupied molecular orbital
multiple linear regression
partial least square
polar surface area
quantitative structure–activity relationship
quantitative structure–pharmacokinetic relationship
total energy of the molecule
apparent volume of distribution
The authors thank Dr. Linping Zhang for synthesis of the 1,4-dihydropyridines and pyridines. Supported in part by a grant from the Kapoor Charitable Foundation (SUNY).
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