JPP 2007, 59: 271–277
© 2007 The Authors
Received January 23, 2006
Accepted August 7, 2006
DOI 10.1211/jpp.59.2.0013
ISSN 0022-3573
271
The use of quantum chemistry in pharmaceutical
research as illustrated by case studies of indometacin
and carbamazepine
, , and
Abstract
A number of case studies that illustrate how quantum chemistry may be used in studying pharma-
ceutical systems are reviewed. A brief introduction to quantum methods is provided and the use of
these methods in understanding the structure and properties of indometacin and carbamazepine is
discussed. The use of calculated structures and molecular electrostatic potentials in developing
quantitative structure–activity relationships is discussed along with the use of computation chemistry
to predict spectroscopic properties.
Introduction
The purpose of this paper is to provide a group of case studies that illustrate how quantum
chemistry may be used in studying pharmaceutical systems. Rather than presenting an
exhaustive literature survey, the focus is on a number of commonly used drugs; namely the
anti-inflammatory drug indometacin and the antiepileptic drug carbamazepine, and how
they have been studied using quantum chemistry. Importantly we focus on existing and
well-established quantum methods. The final section looks forward to how spectroscopic
methods that may be readily applied to solid-state samples, particularly vibrational meth-
ods, may play a role in the future of pharmaceutical research and development.
We are particularly interested in trying to model the properties of molecules, such as
structures, vibrational spectra and charge distributions; for these properties there are an
array of methods and commercial program packages available to researchers (Young
2001). For example, there are comparatively simple molecular mechanics and semi-
empirical methods that may be applied to large molecular systems. These methods have
been successful in many areas (e.g., a recent review by Taskinen et al (2003) highlighted
the use of semi-empirical calculations to predict the octanol–water partition coefficients
for a variety of compounds). AM1 calculations may be used to screen tens of thousands
of compounds for the purposes of drug design as exemplified in the study of ligands for
the retinoic acid receptor by Silva et al (2005). However, as we are interested in molecu-
lar properties such as vibrational spectra it is often necessary to use more sophisticated
and more limited computational methods than offered by semi-empirical approaches.
For this reason we will focus on the use of quantum calculations applicable to these
types of problems.
Hartree-Fock (HF) methods increase accuracy of prediction for vibrational spectra but
scale as a function of the number of electrons in the system and become unwieldy for large
systems (Young 2001). Density functional theory calculations improve on the accuracy of
HF methods but are similarly unwieldy for many-atom (>100 atoms) systems. It is useful
for an appreciation of the utility of these calculations to briefly examine how these methods
accomplish prediction of molecular properties, how they can improve the accuracy of such
predictions and what limitations exist on using such calculations.
Fundamentally the calculations try to determine the energy of the molecule. HF is an ab-
initio method that accomplishes this by getting as close as possible to a solution of the
Schroedinger equation for the molecular system of interest. The Schroedinger equation is
given as:
[PDF]HARTREE–FOCK (HF) METHOD AND DENSITY ...
"1. INTRODUCTION
The methanol-to-gasoline (MTG) process was discovered by accident by researchers at the Mobil Company. This
process provides an alternative to crude oil as a source for gasoline. The process employs a highly selective zeolite
(ZSM-5) catalyst and leads to the synthesis of high-octane gasoline without the need for costly after-production
processing. The process leads to the production of dimethylether, which under the right reaction conditions produces
olefins and eventually paraffins and aromatics. We know that the mixture of these last two is called gasoline.
The MTG [1] process in medium pore-sized aluminosilicate zeolites has been the subject of great theoretical [2–5]
and experimental [1, 6, 7] interest due to its potential industrial importance. Despite this importance, this reaction is not
well understood. The first step in this reaction is believed to be the reaction of two methanol molecules over a suitable
acidic zeolite to give dimethylether and one water molecule:
2CH3OH CH3OCH3 + H2O. (1)
Computing thermodynamical quantities such as ΔrHΘ, ΔrGΘ, and ΔrSΘ is one of the first steps a theoretical or
computational chemist is interested in, since that will help in selecting the appropriate level of theory. Indeed, referencequality
data for thermophysical parameters are a very topical subject. Many studies have been performed to determine
thermodynamical quantities using theoretical methods [8,9]. Both experimental contributions and contributions
describing correlations and modeling are desired.
Hartree–Fock is the most basic ab initio molecular orbital approach. Density functional theory (DFT) is an
approach to the electronic structure of atoms and molecules and states that all the ground-state properties of a system are
function of the charge density. So, DFT calculations cannot be considered a pure ab initio method. In DFT, the electron
density is the basic variable, instead of the wave function. This reduces the computational burden of treating electron–
electron interaction terms, which are treated explicitly as a functional of the density. The DFT approach combines the
capacity to incorporate exchange-correlation effects of electrons with reasonable computational costs and high accuracy.
The past few years has seen a rapid increase in the use of DFT methods"
[PDF]HARTREE–FOCK (HF) METHOD AND DENSITY ...
ajse.kfupm.edu.sa/articles/292A_05P.pdf
by ZS Seddigi - 2004 - Cited by 1 - Related articles
HF calculations at relatively small basis sets are adequate. The theoretical ... experimental results. Keywords: MTG; Hartree–Fock; DFT, vibrational spectra.The methanol-to-gasoline (MTG) process was discovered by accident by researchers at the Mobil Company. This
process provides an alternative to crude oil as a source for gasoline. The process employs a highly selective zeolite
(ZSM-5) catalyst and leads to the synthesis of high-octane gasoline without the need for costly after-production
processing. The process leads to the production of dimethylether, which under the right reaction conditions produces
olefins and eventually paraffins and aromatics. We know that the mixture of these last two is called gasoline.
The MTG [1] process in medium pore-sized aluminosilicate zeolites has been the subject of great theoretical [2–5]
and experimental [1, 6, 7] interest due to its potential industrial importance. Despite this importance, this reaction is not
well understood. The first step in this reaction is believed to be the reaction of two methanol molecules over a suitable
acidic zeolite to give dimethylether and one water molecule:
2CH3OH CH3OCH3 + H2O. (1)
Computing thermodynamical quantities such as ΔrHΘ, ΔrGΘ, and ΔrSΘ is one of the first steps a theoretical or
computational chemist is interested in, since that will help in selecting the appropriate level of theory. Indeed, referencequality
data for thermophysical parameters are a very topical subject. Many studies have been performed to determine
thermodynamical quantities using theoretical methods [8,9]. Both experimental contributions and contributions
describing correlations and modeling are desired.
Hartree–Fock is the most basic ab initio molecular orbital approach. Density functional theory (DFT) is an
approach to the electronic structure of atoms and molecules and states that all the ground-state properties of a system are
function of the charge density. So, DFT calculations cannot be considered a pure ab initio method. In DFT, the electron
density is the basic variable, instead of the wave function. This reduces the computational burden of treating electron–
electron interaction terms, which are treated explicitly as a functional of the density. The DFT approach combines the
capacity to incorporate exchange-correlation effects of electrons with reasonable computational costs and high accuracy.
The past few years has seen a rapid increase in the use of DFT methods"
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