Web Release Date: October 13,
Quantitative Structure-Activity Relationship for Cyclic Imide Derivatives of Protoporphyrinogen Oxidase Inhibitors: A Study of Quantum Chemical Descriptors from Density Functional Theory
and
Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China, and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536
Received June 25, 2004
Abstract:
This study examined the applicability of various density functional theory (DFT)-based descriptors, such as
energy gap (
E) between the highest occupied molecular orbital (HOMO) and the lowest unoccupied
molecular orbital (LUMO), weighted nucleophilic atomic frontier electron density (WNAFED, 
), mean
molecular polarizability (
), and net atomic charge (Qi), in quantitative structure-activity relationship (QSAR)
studies on a class of important protoporphyrinogen oxidase (Protox) inhibitors including a series of cyclic
imide derivatives with various heterocyclic rings and substituents. Our QSAR analysis using the quantum
chemical descriptors calculated at the B3LYP/6-31G(d,p) level led to a useful explicit correlation relationship,
i.e. pI50 = -5.7414 + 0.1424 - 0.00032 - 0.4546
+ 0.2974QN
(n=26, R2=0.87), showing that
descriptors mean molecular polarizability, , and WNAFED 
of a critical carbon atom and net atomic
charge (Qi) in the molecules are most likely responsible for the in vitro biological activity of cyclic imides.
It has been shown that the use of the DFT-based quantum chemical descriptors indeed led to a better QSAR
equation than that obtained from the use of the corresponding descriptors calculated at a semiempirical
PM3 level. The present work demonstrates that the DFT-based quantum chemical descriptors are potentially
useful in the future QSAR studies for quantitatively predicting biological activity, and, therefore, the DFT-based QSAR approach could be expected to help facilitate the design of additional substituted cyclic imide
derivatives of Protox inhibitors with the potentially higher biological activity.
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