Komputasi

Najma Annuria Fithri

2016

Teori Dasar HKSA dan Deskriptor

Theory
Development of a new chemical can be achieved either
by designing a complete new entity or by modifying an
existing one.
Need to possess sufficient knowledge regarding the
nature of the chemical and its potential for interaction
with the biological system.
It is obvious that the biological activity (including toxicity)
and property of any chemical (e.g., drugs,
pharmaceuticals, and carcinogens) depend upon its
interaction with the biological system concerned.
Hence, the primary goal of a chemical designer lies in
establishing a rational explanation of the mechanism of
action of the chemical, which can lead to the derivation
of a suitable theoretical basis and thus enabling the
tailoring of its structure.

 The ligand molecule is recognized by a particular

receptor followed by formation of a ligand-receptor
complex involving different physicochemical forces.
The complex then undergoes some conformational
changes that lead to a series of events giving rise to the
activity.
The features possessed by a chemical entity get
modified during its encounter with the biological system.
Hence, elicitation of biological response is controlled by
the way in which the chemical reacts at the active site of
the biological system. In other words, the biological
system plays a crucial role in determining the structural
features of a chemical needed to elicit a desired
response.

 The pharmacokinetic movements of the drug molecule,

along with its pharmacodynamic properties, are
regulated by a wide number of physical, chemical, and
biological factors (e.g., partitioning behavior, solubility,
pKa value, ionization, interatomic distance, and
stereochemical arrangement), and ultimately contribute
to a considerable degree of complexity and uncertainty
in some cases
The drug molecules and other bioactive chemicals are
considered to interact with macromolecular complexes
present on the cellular surface or inside the cell to elicit a
response.

What is SAR
The structure-activity relationship (SAR) notion attempts to
establish a relationship between various behavioral
characteristics of chemical compounds (namely,
activity/property/toxicity and chemical information
derivable from chemical structures).
Such process involves significant knowledge of
chemistry and physics (defining the compounds),
mathematics (allowing modeling analysis), and biology
(giving reasons for the biological activity profile of
chemicals) to develop a rational basis. I
in other words, the SAR study provides an option to
construct a mathematical equation for a set of chemicals
for their specific activity/property/toxicity behavior using
information about their chemical structure.

Basic Steps in QSAR

1. Data collection/preparation
2. Data processing
3. Data prediction/validation
4. Data interpretation

Physicochemical Characteristics
The kinetics (e.g., movement) and dynamics
(e.g., mechanism of action of chemicals,
including drugs, inside a biological system) are
influenced by the physicochemical properties of
drug molecules.
Three important physicochemical properties
implicated in drug action are
1. hydrophobic
2. electronic and chemical bonding
3. steric features (sterochemical)
which enable a biologically active ligand to interact
with its target receptor

Hydrophobicity
Bioactive membrane are lipoid (lipid bilayer)
Hydrophobicity reflects the ability of ligand to pass through
biological membrane --> Partitioning (partition coefficient)
However, the lipophilicity should be maintained at an
optimum level in order to address two essential factors
[namely, concentration of drug (or other bioactive chemical)
in the extracellular fluid and its elimination from the body].
The n-octanol/water partition coefficient gives a suitable
measure of the hydrophobic behavior of any chemical.
However, features like the chromatographic retention
constant RM and log K0 also give an account of the
lipophilicity measure.
The hydrophobic property of chemicals can also be
theoretically computed for the whole molecule, as well as
for molecular fragments.

Electronic
Drug interaction involves various electronic
attributes for establishing bonding with the target
site since the biological receptors may comprise
amino acid species containing charged and
polar functional groups.
Various types of dispersion forces (charge
transfer complex formation, ionic interaction,
inductive effect, hydrogen bonding, polarization
effect, acidbase catalytic property, etc.)
characterize electronic features.
Two principal forces that rule the behavior of
chemicals are attractive and repulsive forces

Chemical Bonding
1. Covalent Bonding
The covalent bond implicates the strongest bond in the
realm of ligand-receptor interactions.
Such a bond is formed by the share of an electron from
each of the two participating atoms.
In case of drug-receptor interaction, the electrons are
shared by atoms of the ligand and receptor molecule.
The strength of covalent bonds varies from 50 to 150
kcal/mol.
It has been observed that owing to the greater strength of
the covalent bonds, ligands are irreversibly bound to the
receptor when such bonding occurs.

 Example of Covalent Bonding

antagonism of the -adrenoceptor by
phenoxybenzamine through alkylation of an
amino, sulfhydryl, or carboxyl group on the
receptor
blockade of acetylcholinesterase receptor by
organophosphates (dyflos, ecothiophate) by
phosphorylation of an ester bond

2. Ionic Bond
Ionic bonds are formed during attraction of two
ions of opposite charge involving electrostatic
force.
Ionic bonds hold a strength varying between 5 and
10 kcal/mol in an aqueous environment.
The strength of ionic bonds tends to decrease as
two participating atoms are taken apart, and this
decrease has been observed to be proportional
to the squared distance between the atoms

3. Hydrogen Bond
Hydrogen bonding refers to a weak bond
formation between a hydrogen atom attached to
a strong electronegative atom and another atom
of higher electronegativity.
Hence, the hydrogen atom, which is connected
to a highly electronegative atom (e.g., oxygen,
nitrogen, and sulfur) via a covalent bond
develops a partial positive charge and gets
attracted to another strong electronegative atom
(e.g., oxygen, fluorine, nitrogen, and sulfur),
which has developed a partial negative charge
due to attraction between the electron cloud and
its neighbor atom.
The strength of a single hydrogen bond usually
varies from 2 to 5 kcal/mol.

4. Hydrophobic Force
The hydrophobic interaction of molecules
refers to an effect of dislikeness toward
water, that is, insolubility in aqueous
medium.
Formation of such force is favored and
accompanied with a change in entropy of
the system.
At rest, the water molecules remain in an
orderly fashion characterized by reduced
entropy of the system.
The strength of such interaction is 0.37
kcal/mol per-CH2 group.

5. van der Waals Interaction

A van der Waals interaction is a relatively weak force
ranging from 0.5 to 1 kcal/mol and is nonionic in nature.
Neutral molecules containing electronegative atoms, like
oxygen and nitrogen, have a tendency to draw the
electron cloud toward itself through the covalent bond
from its less electronegative neighbor atom.
Such phenomenon institutes a dipolar nature into the
molecule, creating a charge dispersion; that is, a partial
positive (+) as well as a partial negative (-) charge
inside the same molecule.
A weak interaction force is established between opposite
charges (+ and -) of two participating molecules when
they are placed close to each other by aligning the
positive end of one molecule close to the negative end of
the other

van der Waals

Differentiate into 3 forces
Keesom force : If the connection occurs between
two such permanent dipoles, the interaction
becomes much like that of ionic fashion,
although possessing much less strength.
Debye force: A permanent dipole polarizes the
electron cloud in its neighbor molecule, that is,
induced dipole and establishes an interaction
London force: (induced dipole-induced dipole

Other Force and Interaction

Pi-pi stacking interaction
Charge transfer complex
Orbital overlapping interaction

Sterochemical Factor
Consideration of proper optical, geometric,
and conformational specificity can
enhance the drug activity to a very great
extent.
The use of only a single (active)
enantiomer can also reduce the side
effects arising from an inactive
enantiomer.

Isosterism Factor
The notion of chemical isosterism was introduced by
Langmuir to depict similar physical behaviors among
atoms, functional groups, radicals, and molecules.
Langmuirs similarity considered atoms containing
the same number of valence electrons.
The hydride displacement depicts that the same
number of valence electrons is maintained in the
next group element in the periodic table when
hydrogen atom is progressively added to the
previous group element. Hence, OH, NH2, and CH3
groups represent isosters

Objectives of QSAR
Prediction of activity/property/toxicity--> primary
purpose of a QSAR model is to predict the
response value (activity/property/toxicity) of new
chemicals
Reduction and replacement of laboratory
animals --> in 1959 introduction of 3R
(Replacement, Reduction and Refinement)
Virtual screening of library data--> There are
several chemical libraries available containing a
large number of compounds; namely, ZINC,
DUD benchmark, PubChem, ChemBank,
ChEMBL, DrugBank, Interbioscreen, FDA
database, Maybridge, and ChemSpider,

Objectives of QSAR
Diagnosis of mechanism--> For example, chemicals
acting via narcosis have been observed to be well
predicted by lipophilicity measure log P. Here,
partitioning of the chemical accounts for its accumulation
in the lipid layer and therefore acts as the prerequisite for
the mechanism involved.
Classification of data --> QSAR provides an option for
performing a classification analysis (like discriminant
analysis) to such response values and thereby
categorizing the compounds into different
semiquantitative categories
Optimization of leads--> QSAR can provide a rational
guidance for the design of new compounds obtained
from a chemical data screening

Objectives of QSAR
Refinement of synthetic targets --> Design of
synthetic drug molecules can be fine-tuned by
using the knowledge of existing/developed QSAR
models.
Example: It was reported that a potent cardiotonic
agent, the 2,4-dimethoxy analogue of sulmazole
depicted CNS side effects termed bright vision in
patients during the clinical trial stage. The log P of
the compound was 2.59, causing the molecule to
penetrate the CNS of the trial patients. Then
replacement of the 4-methoxy group with 4S(O)CH3 led to the development of sulmazole
molecule possessing log P value of 1.17 and
bearing no such CNS side effects.

QSAR

 In the beginning of the 1960s, Corwin

Hansch, also known as the Father of
modern QSAR, provided further
momentum to QSAR research by using
Hammett constants and hydrophobicity
parameters to develop correlation models
on plant growth regulators

Descriptors

Definition
Molecular descriptors are terms that
characterize specific information about a
studied molecule.
They are the numerical values associated
with the chemical constitution for
correlation of chemical structure with
various physical properties, chemical
reactivity, or biological activity

Type of descriptors

Physicochemical
Structural
Topological
Electronical
Geometric
Quantum chemical

Descriptor Common in QSAR

1. Physicochemical Descriptors
a. Hydrophobic Parameters
-Partition Coefficient (log P)
Compounds for which P>1 are lipophilic or
hydrophobic, and compounds for which
P<1 are hydrophilic
- Hydrophobic Constant ()
- Hydrophobic fragmental constant (f, f')

 Electronic parameters
- pKa
- Hammett constant
-

 Steric parameter
- Taft steric constant
- Charton steric parameters and van der
Waals radius
- Effective Charton steric parameters
- STERIMOL parameters
- Molar refractivity
- Parachor

Quantum descriptors
Mulliken atomic charges
Quantum topological molecular indices

Spatial Parameters

Radofgyration
Jurs descriptors
Shadow indices
Molecular surface area
Density
Principal moment of inertia
Molecular volume