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Molecular Descrip

Chapter 3 discusses molecular descriptors, which are numerical values that characterize properties of molecules and can be derived from chemical structures. It covers various types of descriptors, including those based on simple counts, physicochemical properties like hydrophobicity, and more complex 2D and 3D representations. The chapter emphasizes the importance of these descriptors in analyzing large datasets and their application in predicting molecular properties.

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2 views2 pages

Molecular Descrip

Chapter 3 discusses molecular descriptors, which are numerical values that characterize properties of molecules and can be derived from chemical structures. It covers various types of descriptors, including those based on simple counts, physicochemical properties like hydrophobicity, and more complex 2D and 3D representations. The chapter emphasizes the importance of these descriptors in analyzing large datasets and their application in predicting molecular properties.

Uploaded by

olivespharm
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Chapter 3

MOLECULAR DESCRIPTORS

1. INTRODUCTION

The manipulation and analysis of chemical structural information is made


possible through the use of molecular descriptors. These are numerical values
that characterise properties of molecules. For example, they may represent the
physicochemical properties of a molecule or they may be values that are derived
by applying algorithmic techniques to the molecular structures. Many different
molecular descriptors have been described and used for a wide variety of purposes.
They vary in the complexity of the information they encode and in the time
required to calculate them. In general, the computational requirements increase
with the level of discrimination that is achieved. For example, the molecular
weight does not convey much about a molecule’s properties but it is very rapid
to compute. By contrast, descriptors that are based on quantum mechanics may
provide accurate representations of properties, but they are much more time-
consuming to compute. Some descriptors have an experimental counterpart (e.g.
the octanol–water partition coefficient), whereas others are purely algorithmic
constructs (e.g. 2D fingerprints).

In this chapter we will describe commonly used molecular descriptors that can
be applied to relatively large data sets. These include descriptors that represent
properties of whole molecules such as log P and molar refractivity; descriptors
that can be calculated from 2D graph representations of structures such as
topological indices and 2D fingerprints; and descriptors such as pharmacophore
keys that require 3D representations of structures. We conclude by considering
how descriptors can be manipulated and combined together. Our emphasis will be
on descriptors that are properties of the whole molecule, rather than of substituents.
The latter type of descriptor was very important in the development of QSARs, and
will be briefly covered in Chapter 4.

53
54 An Introduction to Chemoinformatics

2. DESCRIPTORS CALCULATED FROM THE 2D


STRUCTURE

2.1 Simple Counts

Perhaps the simplest descriptors are based on simple counts of features such
as hydrogen bond donors, hydrogen bond acceptors, ring systems (including
aromatic rings), rotatable bonds and molecular weight. Many of these features
can be defined as substructures or molecular fragments and so their frequency
of occurrence can be readily calculated from a 2D connection table using the
techniques developed for substructure search. For most applications, however,
these descriptors are unlikely to offer sufficient discriminating power if used in
isolation and so they are often combined with other descriptors.

2.2 Physicochemical Properties

Hydrophobicity is an important property in determining the activity and


transport of drugs [Martin and DeWitte 1999, 2000]. For example, a molecule’s
hydrophobicity can affect how tightly it binds to a protein and its ability to
pass through a cell membrane. Hydrophobicity is most commonly modelled
using the logarithm of the partition coefficient between n-octanol and water
(log P). The experimental determination of log P can be difficult, particularly for
zwitterionic and very lipophilic or polar compounds; data are currently available
for approximately 30,000 compounds only [Mannhold and van der Waterbeemd
2001]. Of course, there are no data for compounds not yet synthesised. There
is thus considerable interest in the development of methods for predicting
hydrophobicity values.

The first approach to estimating log P was based on an additive scheme


whereby the value for a compound with a substituent X is equal to the log P for the
parent compound (typically chosen to be the molecule with the substituent being
hydrogen) plus the appropriate substituent constant π X [Fujita et al. 1964]. The
substituent constants, π X , were calculated from experimental data as follows:

π X = log PX − log PH (3.1)

While the approach worked well within a congeneric series of compounds, the
π-values were found not to be additive across different series. For example, it is
inappropriate to use π-values derived from a benzene parent on electron-deficient
rings such as pyridine.

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