a summary of all the methods to designing the enzyme inhibitors for the Drug designing....

1. Approaches to design enzyme inhibitors
 Made by:- Aanshi Srivastava
 Roll No.:- 1/20/FET/BBT/001
 Submitted To:-
Dr. Rashmi Rameshwari
(Associate Professor)

2. • INTRODUCTION
• Designing enzyme inhibitors is a crucial aspect of drug development,
especially in the field of pharmacology and medicinal chemistry.
Enzyme inhibitors are compounds that can selectively block the
activity of specific enzymes, which play essential roles in various
biological processes. There are several approaches to designing
enzyme inhibitors, each with its own advantages and challenges

3. • Structure-Based Drug Design (SBDD)
• This approach relies on the detailed knowledge of the three-dimensional
structure of the enzyme of interest. SBDD involves the following steps:
• Crystallography or NMR Studies: Determine the crystal structure or NMR
structure of the enzyme with or without its substrate or cofactors.
• Virtual Screening: Use computational methods to screen a library of small
molecules or compounds to identify potential inhibitors that can bind to the
active site or allosteric sites of the enzyme.
• Rational Design: Based on the structural information, design or modify
compounds to optimize their binding affinity and specificity to the enzyme's
active site.

4. • Fragment-Based Drug Design (FBDD)
Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery
(FBDD) is a method used for finding lead compounds as part of the drug discovery process.
Fragments are small organic molecules which are small in size and low in molecular weight.
The fragment based drug design starts with the identification of fragments or low molecular
weight compounds that generally bind with weak affinity to the target of interest. The
fragments that form high quality interactions are then optimized to lead compounds with
high affinity and selectivity.
In Fragment Based Drug Designing, the researchers start with small fragments of molecules
known as "fragment libraries" that have high binding affinities but low molecular weights.
These fragments are then systematically combined and modified to create larger molecules
with improved binding properties.

5. • Pharmacophore-Based Design
Pharmacophore models are built by using the structural information about the active
ligands or targets.
The pharmacophore models developed are used to identify novel compounds that satisfy
the pharmacophore requirements and thus expected to be biologically active.
Pharmacophoric modelling is based on the theory that having common chemical
functionalities, and maintaining a similar spatial arrangement, leads to biological activity
on the same target.
The pharmacophore based drug designing approach relies on identifying the essential
structural and chemical features (pharmacophores) required for a molecule to interact with
the enzyme.
 Computational methods can then be used to search databases for compounds that match
these pharmacophores.

6. • Quantitative Structure-Activity Relationship
(QSAR) Analysis
QSAR involves analyzing the relationship between the chemical
structure of a series of compounds and their biological activity.
This information is used to predict the activity of new compounds and
guide their design.
It is based on the idea that when we change a structure of a molecule
then also the activity or property of the substance will be modified.

7. • High-Throughput Screening (HTS)
In HTS, a large library of compounds is tested against the enzyme of
interest to identify potential inhibitors.
 This approach is useful for identifying lead compounds but may not
provide detailed insights into the binding mechanism.
 This is a drug discovery process that allows automated testing of
large numbers of chemical and/or biological compounds for a specific
biological target, for example through binding assays.

8. • Natural Product-Based Design
Natural products are important sources for new drugs and are also good lead
compounds suitable for further modification during drug development
Natural products often contain bioactive compounds that can serve as starting points
for designing enzyme inhibitors.
 Researchers can isolate, modify, or synthesize analogues of natural products to
improve their activity and specificity.
The first commercial pure natural product introduced for therapeutic use
is morphine marketed by Merck in 1826, and the first semi-synthetic pure drug
aspirin, based on a natural product salicin isolated from Salix alba, was introduced
by Bayer in 1899.

9. • Allosteric Inhibition
 When an inhibitor binds to the enzyme, all the active sites of the protein
complex of the enzyme undergo conformational changes so that the activity of
the enzyme decreases. In other words, an allosteric inhibitor is a type of
molecule which binds to the enzyme specifically at an allosteric site.
Instead of targeting the enzyme's active site, allosteric inhibitors bind to sites
on the enzyme away from the active site, causing a conformational change that
inhibits enzyme activity. Identifying allosteric sites and designing compounds
that bind to them is a challenging but valuable approach.
 2 Types :- : noncompetitive inhibition and uncompetitive inhibition

10. • Covalent Inhibition
Covalent drugs are also discovered through electrophile-first approaches,
meaning that the initial discovery process is rooted in finding a covalent
ligand from the outset, instead of incorporating covalency into a known
reversible ligand.
Some inhibitors form covalent bonds with the enzyme, irreversibly
inhibiting its activity.
 Careful design is required to ensure selectivity and minimize off-target
effects.

11. • Peptide and Protein Inhibitors
The primary use of protein structure for the development of drug compounds
is to determine the structure of a protein in complex with a tool compound (a
known ligand or lead inhibitor) for the purpose of suggesting a new chemical
hypothesis in order to improve inhibitor affinity by suggesting new chemical
modifications
Designing peptides or proteins that mimic the natural substrate or interact
with the enzyme's active site can also be an effective approach to enzyme
inhibition.
Only peptides containing proteinogenic amino acids, rather than NRPs, are
produced in the phage. This high-throughput sequencing method can be used
to identify drug leads, including antibodies and peptides

12. • Computational Approaches
Computational drug discovery is an effective strategy for accelerating
and economizing drug discovery and development process.
Computational methods, such as molecular docking, molecular
dynamics simulations, and machine learning algorithms, play a
significant role in predicting and optimizing enzyme inhibitors.
It has the ability to fast-track the process of hit identification, hit to
lead, and lead optimization

13. • NOTES
The choice of approach depends on the specific enzyme target, available
structural information, resources, and the desired properties of the
inhibitor.
Often, a combination of these approaches is used to optimize the design
of enzyme inhibitors for therapeutic or research purposes.