Paper No.

: 06 Computational Biology

Module : 09 Chemical Functional Descriptors - II

Principal Investigator: Dr. Vibha Dhawan, Distinguished Fellow and Sr. Director
The Energy and Resources Institute (TERI), New Delhi

Co-Principal Investigator: Prof S K Jain, Professor,

Jamia Hamdard University, New Delhi

Paper Coordinator: Dr. Indira Ghosh, Professor

Jawaharlal Nehru University, New Delhi

Content Writer: Dr. Indira Ghosh, Professor

Jawaharlal Nehru University, New Delhi

Paper Reviewer: Dr. Debasisa Mohanty

National Institute of Immunology, New Delhi

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 Description of Module
Subject Name Biotechnology

Paper Name Computational Biology

Module Name/Title Chemical Functional Descriptors - II

Module Id 09

Pre-requisites

Objectives

Keywords

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 P06-module 9 : Chemical Descriptors

The topics will discussed what are Descriptors , how to derive Descriptors from chemical

structures,2D later we shall find how to construct 3D structure

What kinds of properties are relevant to biological functions? We shall start with 2D

descriptors, like using SMILES to chemical structure and then derive the descriptors. Just by

counting atoms we can get MW which is very effective descriptors, similarly counting many

important properties like hydrogen bond donors/acceptors, aromatic rings, rotatable bonds

etc. will provide good correlation with molecule’s biological functions. From such simple

descriptors we can proceed to find more complicated like topological and electronic

descriptors, these are found to be highly correlated to the physico -chemical properties of the

chemicals. Descriptors are chemical characteristic of compounds which explain the relevant

biological properties. Many structure based descriptors available, but molecular descriptors

are also very important like cLogP , which is directly connected with the hydrophobic

property of molecule.

Topological Descriptors are derived from structural connectivity as shown in figure here for

Tyrosine. Connection table or Distance matrix are also used as topological descriptors.

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 13
OH

11 9

12 8

6
CH2
5
H2N CH
4

O OH
3 1

• 1 2 3 4 5 6 7 8 9 10 11 12 13
1.O 1 2 2 3 3 4 5 6 7 6 5 8
2.1 C 1 1 2 2 3 4 5 6 5 4 7
3.2 1 O 2 3 3 4 5 6 7 6 5 8
4.2 1 2 C 1 1 2 3 4 5 4 3 6
5.3 2 3 1 N 2 3 4 5 6 5 4 7
6.3 2 3 1 2 C 1 2 3 4 3 2 5
From this connectivity matrix one can derive Weiner Index which has strong correlation with
7.4 3 4 2 3 1 C 1 2 3 2 1 4
boiling point of alkanes. It is given by ,
8.5 4 5 3 4 2 1 C 1 2 3 2 3
9.6 5 6 4 5 3 2 1 C 1 2 3 2
10. 7 . 6Similarly 7 Zagreb
5 6index4can 3also be2derived
1 from C each1 non-hydrogen
2
atom, add1up the squares of the number of connections to other non-hydrogen atoms
11. 6 5 6 4 5 3 2 3 2 1 C 1
(regardless of bond order) and given by
2
12. 5 4 5 3 4 2 1 2 3 2 1 C
3 A few examples are worked out in slides.
13. 8 7 8 6 7 5 4 3 2 1 2 3
O
Electronic descriptors depict the property related to valence of bonded atoms, like value

which is given byh where  is count of electrons in sigma orbital and h is count of

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 bonded hydrogen atoms. Simple descriptors like this explains many electronic behaviour

of the molecule like The count of adjacent atoms excluding hydrogens , count of sigma

electrons on an atoms excluding H, count of bonds joining to an atoms excluding H and

immediate topological environment of the atom in the molecule, so many important

characteristics are included in one descriptor , this explains why using descriptors one can

correlate many biological property of chemicals.

There are 4 quantum numbers as defined in the slides and a very important descriptor

called Kier-Hall electronegativity value can be derived from this quantum numbers.

From molecular connectivity some more important indices can be derived which

quantifies the shape & structure of chemicals. The Kappa shape indices are the basis of a

method of molecular structure quantification in which attributes of molecular shape are

encoded into three indices (Kappa values). These Kappa values are derived from counts

of one-bond, two-bond and three-bond fragments, each count being made relative to

fragment counts in reference structures which possess a maximum and minimum value

for that number of atoms. Many such descriptors are discussed in the slides and relevant

biological relationships are shown.

Some other molecular properties are also used as descriptors like clogP, which is octanol-

water partition coefficient; this has been found very useful in predicting the

bioavailability of a drug. Because a drug needs to be soluble enough in lipid to be able to

cross cell membranes but soluble enough in water not to get stuck there, many methods

have been proposed for calculating appropriate estimation of this property from

structures. One such starting estimation was proposed by Corwin Hansch and Al Leo at

Pomona College using a good set of chemicals whose clogP experimentally known and

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 using the fragment method a statistically relevant correlation was developed. Later many

such methods are developed.

Atom based descriptors are also been very effective to predict molar refractivity, charged

partial surface area and intestinal absorption of drugs.

It is noted that seminal works were done to convert from simple SMILES to a 3D

structure depictions by several SW like CONCORD (Texas, 1987), CORINA

(Munich/Erlangen, 1990) & OMEGA ( Open Eye , ~2000 ). Each of them use very

elegant methods to convert the chemical 2D structure into perfect stereochemically

distinct and flexible 3D structures, however x-ray crystallography on small molecules are

already been collected and available with Experimental data in Cambridge Structure

Database.

Milestones in molecular modeling & Chemoinformatics came due to the ligand based

superposition of active site; it is common that if the different compounds bind to the same

active site, they must have a kind of 3D superposition. It can be by the structural

superposition as shown in some cases, but more appropriately it needs to be similar by

complementary interactions (pharmacophore feature based ) occurring at the active site,

so a substructure based searching became quite relevant. More important method was

developed which takes care of the interaction energy surrounding the molecules which

bind to the same active site, it is called comparative molecular field analysis driven

superposition of ligands.

Computational Biology
Biotechnology
Chemical Functional Descriptors - II
 Similar approach also has been seen using graph similarity in the structural superposition

amongst different size of proteins .An example of such case has been shown here. Similar

computational tools are used for ligand superposition and protein superposition.

One exercise has been given for students to learn and verify the SMILES depiction, this

can be used for different descriptor calculations.

Computational Biology
Biotechnology
Chemical Functional Descriptors - II