In-Silico Drug Designing

• Drug discovery and development

Drug discovery is the process through which a drug candidate is identified and
partially validated for the treatment of a specific disease. It involves a wide range of
scientific disciplines including biology, chemistry and pharmacology. The main
purpose of developing a drug is to address the public health concern. It involves two
stages, first is drug discovery and second is drug development. Both the stages are
very complex and time consuming.
Drug discovery (Stage I) involves the following steps:
i. Target identification- In this we identify the gene/protein that is involved in a
disease or causes the disease
ii. Target validation- Out of various proteins that have been identified we need to
check which one is particularly involved in that disease and validate it
iii. Lead identification- Lead is a compound that has the greatest potential to bind
to our target successfully. So, we need to identify that lead from a library
consisting of thousands of compounds.
iv. Lead optimisation- Once we have found the lead, we need to modify it to
increase the drug likeness properties to make it suitable and efficient for
public.
Drug development (Stage II) involves the following steps:
i. Pre-clinical trials- Before the drug is launched in the market it needs to be
tested first. So, first it is tested on animals to check its efficiency.
ii. Clinical trials- In this, the drugs are tested on humans in small dosages who
have volunteered for the same
iii. Regulatory approval- After the trials are successful, the drug is sent for
approval from the FDA
iv. Sales and marketing- If the drug is approved by the FDA it is launched in the
market for public use

• Computer aided drug discovery (CADD)

Computer aided drug discovery (CADD) represents computational methods and
resources that are used to facilitate the design and discovery of new therapeutic
solutions. Over the last few years, computer aided drug design (CADD) also known
as in silico screening has become a powerful technique because of its utility in various
phases of drug discovery and development through various advanced features. In
silico screening also paves path for the synthesis and screening of selected compounds
for better therapeutics. These methods can help in identifying drug targets via
bioinformatics tools. They can also be used to analyse the target structure for possible
binding/active sites, generate candidate molecules, check for their likeness, dock these
molecules with the target, rank them according to their binding affinities, further
optimize the molecule to improve binding characteristic.
Computational methods are based on the fact that any compound which is
pharmacologically active acts through interaction with targets like proteins and
nucleic acids. Major factors are molecular surface, electrostatic force, hydrophobic
interaction and hydrogen bond formation which govern such type of molecular
interactions between drug and receptor. These are only factors which are considered
at the time of analysis and prediction of interaction between two molecules. CADD
designs any product in a documented way and facilitates the process of
manufacturing. The compounds which have to be tested can be from various natural
sources like plants, animals, microorganisms and also synthetic. After testing; test
compound can be accepted or rejected according to result like absence/presence of
toxicity or carcinogenicity, synthesis is complex, insufficient efficiency, etc.

• Types of drug discovery

There are two types of drug discoveries which are as follows-
i. Ligand based discovery:

- It relies on knowledge of other molecules that bind to the biological target

of interest
- It is used to derive a pharmacophore model that defines the minimum
necessary structural characteristics a molecule must possess in order to
bind to the target
- Alternatively, a quantitative structure-activity relationship (QSAR), in
which a correlation between calculated properties of molecules and their
experimentally determined biological activity, may be derived. These
 QSAR relationships in turn may be used to predict the activity of new
analogues

ii. Structure based discovery:

- It relies on knowledge of the three-dimensional structure of the biological

target obtained through x-ray crystallography and nuclear magnetic
Resonance (NMR) spectroscopy
- Using the structure of the biological target, candidate drugs that are
predicted to bind with high affinity and selectivity to the target may be
designed using:
1) interactive graphics
2) Intelligence of a medicinal chemist.
3) various automated computational procedures may be used to suggest
new drug candidates.

• Methods for drug discovery

1) Virtual screening: The first method is identification of new ligands for a given
receptor by searching large databases of 3D structures of small molecules to find
those fitting the binding pocket of the receptor using fast approximate docking
programs.
2) de novo design of new ligands: In this method, ligand molecules are built up within
the constraints of the binding pocket by assembling small pieces in a stepwise
manner. These pieces can be either individual atoms or molecular fragments. The key
advantage of such a method is that novel structures can be suggested.
3) optimization of known ligands by evaluating proposed analogues within the
binding cavity.

• Advantages of CADD

- Time effective
- Cost effective
- Accuracy
- Information about the disease
- Screening is reduced
- Database screening
- Less manpower is required