Name: SATWIK PATRO Reg. No.

: 21BCM0033

CHEMISTRY DIGITAL ASSIGNMENT-2

The Role of Computational Chemistry for Development of
Drugs and Functional Materials

❖ DRUGS: -
A drug is a chemical entity that when consumed/injected results in control/eradication
of an infection/disease, or to improve physical or mental well-being in any other way.

❖ COMPUTER CHEMISTRY: -
It is the branch of chemistry that uses the results of theoretical chemistry
incorporated into efficient computer programs to assist solving chemical problems,
analyzing data obtained in complex experiments like physical and chemical
properties of molecules; and sometimes used to predict new molecules or new
reactions which are later investigated experimentally.

❖ HISTORY OF DRUG DESGIN: -

• In early 19th century plants and animals were are source for medical substance.
a) Late 19th century - fewer natural products used, more synthetic substances. Dye and
chemical companies start research labs and discover medical applications. (Bayer)
b) 1905 - John Langley: Theory of receptive substances which stated "The concept
of specific receptors that bind drugs or transmitter substances onto the cell,
thereby either initiating biological effects or inhibiting cellular functions"
c) 1909 - First rational drug design Goal: safer syphilis treatment than Atoxyl.

1 | Page
 Paul Erhlich and Sacachiro Hata wanted to maximize therapeutic index
Synthetic: 600 compounds; evaluated ratio of minimum curative dose and
maximum tolerated dose. They found Salvarsan (which was replaced by
penicillin in the 1940's).
d) 1960 - First successful attempt to relate chemical structure to biological action
quantitatively.
e) Mid to late 20th century - understand disease states, biological structures,
processes, drug transport, distribution, metabolism. Medicinal chemists use this
knowledge to modify chemical structure to influence a drug's activity, stability,
etc.

❖ Importance Computational methods used in Drug Discovery: -

• Prognosis of side effects: - Drugs are chemical compounds that are consumed by
humans. First the drugs are clinically tested to observe the favorable or unfavorable
changes in the human body.
• These laboratory experiments are costly as well as prolonged.
➢ An alternate solution to these techniques is provided through the computational
methods.
➢ This field aims to summarize the important studies and contributions in the field of
drug side effect prediction by computational techniques.

❖ Computer-Aided Drug Design (CADD): -

• It is a computational chemistry to discover, enhance or study drugs and related
biological active molecules.
• ADVANTAGES OF CADD: -

2 | Page
• Traditional experimentation which requires animal and human models can be
replaced by CADD, saving both time and cost and Less manpower is required.
• We can get detailed information about the disease.
• Screening for experimental testing is reduced, a smaller set of compounds is
selected from large
• CADD also leads to the construction of high-quality datasets and libraries that
can be optimized for high molecular diversity or similarity
• CADD increases accuracy.
• Flowchart for CADD: -

• FLOWCHART:
CADD APPROACHES
-

LIGAND BASED
STRUCTURE BASED

CRYSTAL HOMOLOGY
STRUCTURE MODELLING QSAR LEAD
ANALYSIS
IDENTIFICATION

COMPUTATIONAL ANALYSIS
OF PROTIEN LIGAND
INTERACTION

IN SILICO-SOLUBILITY, BBB
MODIFICATION OF LIGAND
& TOXICITY PREDICTION
WITHIN THE ACTIVE SITE FOR
BETTER DESIGN

PRECLINICAL TRAIL LEAD OPTIMIZATION

3 | Page
 ❖ STRUCTURE BASED DRUG DESIGN or DIRECT DRUG
DESIGN: -
• It is one of the of the first technique to be used in drug design that is helped in
discovery process of drugs.
• PROCEDURE: -
i. It relies on knowledge of the three-dimensional structure of the biological target
obtained through methods such as x-ray crystallography or NMR spectroscopy.
 x-ray crystallography

 NMR spectroscopy

ii. If an experimental structure of a target is not available, it may be possible to create

a homology model of the target based on the experimental structure of a related
protein.

4 | Page
iii. Using the structure of the biological target, candidate drugs are predicted to bind
with affinity and selectivity to the target may be designed using interactive graphics
and the institution of a medicinal chemist.
• FLOWCHART: -
STRUCTURE-BASED DRUG
DESIGN

3D STRUCTURE DETERMINATION

SITE REPRESENTATION

SITE IDENTIFICATION/CHARACTERIZATION

LIGAND GENERATION

DOCKING DE NOVO DESIGN

SCORING

❖ LIGAND BASED DRUG DISCOVERY: -

• The first category is about finding ligands for a given receptors, which is usually
referred to as database searching.
• Then a large number of potential ligand molecules are screened.
• This method is usually referred as ligand-based drug design.
• It saves synthetic effort to obtain new lead compounds.
• Often, computational tools such as pharmacophore models or the shape of the
compounds can be useful for design purposes.

5 | Page
 • Once a dataset of considerable size becomes available, with a good range of
potency, a Quantitative Structure-Activity Relationships (QSAR) model can be
attempted and used if the models are robust enough for prediction purposes

LIGAND BASED
DRUG
DISCOVERY(LBDD)

QSAR LEAD
IDENTIFICATION

Lead Optimization
In-Solubility,
BBB& Toxic
Prediction
Preclinical Trails

a) DOCKING: -
➢ It gives a prediction of ligand-receptor complex structure using computation
methods.
➢ It includes finding the right key for the lock where sampling confirmation of
ligands is done in active site of proteins then ranking this confirmation via
scoring function.
➢ Given two biological molecules determine:
o Whether the two molecules “interact”;
o If so, what is the orientation that maximizes the “interaction” while
minimizing the total “energy” of the complex.

LIGAND TARGET PROTIENS

DATABASE

MOLECULAR
DOCKING
LIGAND DOCKED INTO
PROTIENS ACTIVE SITE

PHARMACOKINETIC AND PHARMACODYNAMIC OPTIMIZATION

6 | Page
b) DE NOVO APPROCHES: -
• It is the approach to build a customized ligand for a given receptor.
• The approach involves the ligand optimization.
• Ligand optimization can be done by analyzing protein active site properties that
could be probable area of contact by the ligand.
• The analyzed active site properties are described to negative image of protein such
as hydrogen bond, hydrogen bond acceptor and hydrophobic contact region.
3D STRUCTURE OF RECEPTOR ARE
USED TO DESIGN NEWER MOLECULES INVOLVES STRUCTURAL
DETERMINATION OF THE LEAD
TARGET COMPLEXES AND LEAD
MODIFICATIONS USING
INFORMATION AVAILABLE ABOUT MOLECULAR MODELLING TOOLS
TARGET RECEPTOR BUT NO EXISTING
LEADS THAT CAN INTERACT

 QSAR: -
• A QSAR is a mathematical
relationship (in form of an
equation) between a
biological between a
biological activity of a
molecular system and its
geometric and chemical
characteristics.

• Basically, it is approach
attempts to identify and
quantify the physiochemical
properties of a drug and to
see whether any of these
properties has an effect on
drugs biological activity.

 LEAD IDENTIFICATION: - The organic compounds are identified which

interact with the target protein and modulate its activity by using random (screening)
or rational (design) approaches.

7 | Page
❖ Virtual Screening and Molecular Docking for Drug Discovery: -
• These are computational technique based used in drug discovery to search
libraries of small molecules in order to identify, those structures which are most
likely to bind/interact to a drug target, typically a protein, receptor or enzyme

ROLE OF COMPUTATIONAL CHEMISTRY IN

DEVELOPMENT OF DRUGS: -
As a result, we may conclude that computational approaches have been very beneficial
and play an important part in today’s generation
Each computational method is best suited to a specific stage of drug development.
Indeed, it has been increasingly clear over the last two decades that computational tools
help speed up the identification, design, and optimization of small compounds as
potential therapeutic candidates. SBDD techniques are more suited to the phase of hit
identification and lead generation, where new active small compounds are created,
discovered, and turned into powerful inhibitors. When drug-like qualities are tweaked
to promote efficacy and reduce attrition in drug development, QSAR approaches are
usually preferable. Approaches that were historically prohibitive for effective drug
design, such as molecular dynamics simulations and Quantum Mechanics-based

8 | Page
methods, are now commonly utilized in all phases of the drug development pipeline,
widening the computational arsenal of drug discovery. The mass manufacture of
pharmaceuticals and medicines has become possible because to advances in technology.
With the current state of affairs, new viruses and diseases emerge as the days pass, and
these technological advancements. All of these are being addressed as a result of
improvements. Molecular dynamics and first-principles simulations will become more
widely used as faster algorithms and better computer technology become available. As
a result, we expect computational chemistry tools to have a stronger impact on drug
development in the next years. In the last ten years, the rate of discovery of disease-
related targets has outpaced the rate of discovery of therapies. Computational methods
such as protein structure prediction methods, virtual high-throughput screening, and
docking methods have been used to speed up the drug discovery process with a
significant increase in the number of drug targets, and are now routinely used in
academia and the pharmaceutical industry. These strategies are well-established and
have demonstrated considerable promise and success as a valuable component of the
drug discovery pipeline. Computationally predicting and filtering massive molecular
datasets and selecting the most promising molecules to be optimized is cheaper and
faster. In vitro screening will be limited to compounds anticipated to exhibit the desired
biological activity. This saves money and time by reducing the danger of wasting
resources on potentially ineffective molecules that would otherwise be examined in
vitro.

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
SATWK.J. PATRO
21BCM0033

9 | Page