CIA 1

Topic: A written report on fundamental biochemical concepts of drug design

and its

relationship to receptors, its dynamics, and latest trends in drug design in

not more than 1000 words with illustration with appropriate flow chart

diagram

for clear depiction of the process.

Submitted by: N Asmita Bandyopadhyay (2233645)

Submitted to: Dr Nesin Mathew

Life indeed is a blessing. The collective drive to live is unwavering to experience the world's

wonder and beauty wonder and beauty. Since the dawn of time, people have worked to extend

their life expectancy, which now is 73.16 years. All of this is a miracle of drugs and medicines,

which are substances with the therapeutic value used to prevent, identify, cure, or relieve the

symptoms of a disease or other abnormal state.

Drug Design:

The development of drugs through studying the structures and functions of target molecules is

regarded as rational drug design. It entails researching how a drug works, how it reacts to

produce pharmacological effects, and how it is metabolised and thus eliminated from an

organism.

Modern drug design begins with determining the cause of the disease state, followed by

determining the specific site that is causing it. A chemical compound known as the Lead

Compound that shows promise as a treatment for a disease is sought after, leading to the

development of a new drug. There are numerous ways to locate a lead compound. This includes

clinical observations, in which a drug candidate exhibiting multiple pharmacological effects

during clinical trials is used in a secondary activity, and focused screening, in which compounds

with different functional groups than the lead are tested and random screening tests numerous

chemical compounds in a bioassay.

Rational Drug Designing:

● Computer-aided drug design: encompasses developing and analysing drugs and related

physiologically active substances using computer methodologies. It is crucial because of

its improved selectivity, effectiveness, efficiency, short duration, minimal toxicity, and

better match with pharmacokinetic parameters. Types of CADD are:

1) Ligand-based drug design: In the lack of 3D receptor information, this method

depends on knowledge of the compounds that bind to the desired biological

target. The most significant and often employed methods in this are 3D

quantitative structure-activity correlations and pharmacophore modelling.

2) Structure-based drug design: This is based on the information available about the

structure of the target to which the drug will bind. This process combines virtual

screening and de novo drug design. The first step in structure-based drug design

is to identify the target protein. The following step is to locate the binding pocket

where the ligand binds and exerts its therapeutic effect. Molecular docking is a

virtual simulation technique used to model the atomic interaction of a small

molecule and a protein.

Drug Designing also involves the study of structure–activity relationships (SARs) defined as an

array of powerful drug design technologies to study the relationships between the chemical

structure of a led compound and the biological activity of a molecule. It includes the study of the
Size and shape of the carbon skeleton, degree of substitution and stereochemistry. It also includes

Quantitative SARwhere mathematical relationship in the form of an equation between biological

activity and measurable physicochemical parameters. These parameters are used to represent

properties such as lipophilicity, shape and electron distribution, which are believed to have a

major influence on the drug’s activity.

Pharmacodynamics:

Pharmacodynamics is derived from the Greek words "pharmakon" (drug) and "dynamikos"

(power). It is the investigation of a drug's molecular, biochemical, and physiologic effects.

1. Receptor: It is defined as a molecule that recognizes a particular small molecule whose

binding brings about the regulation of a cellular process. The important receptors to

which drugs bind are:

a. Ligand-gated ion channels are ionotropic receptor that is characterised by the

binding of an extracellular ligand, which causes a change in the protein structure

and the transient passage of ions such as sodium, potassium etc through a

transmembrane pore. Sometimes, the opposite is true: the channel closes upon

ligand binding. Changes in ion levels within the cell can alter the activity of other

molecules, such as ion-binding enzymes, causing a response. LGIC can be

purinoreceptors, glutamate receptors, or Cys-loop receptors.

b. Tyrosine-Kinase coupled receptors: are embedded in the plasma membrane, with

tyrosine molecules lodged intracellularly. When a ligand binds to the extracellular

side of a TKLR, two TLKRs combine to form a dimer, a supramolecular complex

of two proteins. Then phosphorylation occurs, resulting in the formation of a

phosphorylated dimer. Then receptor binds to key proteins inside the cell, which

allow the extracellular ligand signal to enter the cell.

c. G-Protein-coupled receptors: are also cell membrane-spanning receptor proteins.

When a ligand binds on the extracellular side of a GPCR, conformational changes

take place on the intracellular side which causes the release of proteins into the

cytosol which transmit the signal of the ligand and ultimately causes cellular

change.

d. Intracellular receptors are generally reserved for highly lipid-soluble drugs such

as anti-inflammatory steroids, thyroid hormones, and vitamin A or D. When

activated by the binding of an agonist, they translocate to the nucleus of the cell

and recognize specific binding sites along the chromosomal DNA called response

elements which when activated, alter patterns of gene expression. These drugs

have a slow onset of action and a much longer duration of action.

2)Some Theories of drug-receptor interaction:

1. Occupancy Theory: Gaddum and Clark propose that the severity of the

pharmacological effect is proportional to the number of receptors occupied by the

drug.

2. Rate Theory: It suggests that pharmacological activity is proportional to the rate

of drug association and dissociation with the receptor.

 3. Induced Fit Theory: The receptor need not be in the correct conformation to bind

to the drug. As the drug approaches the receptor, a conformational change occurs,

orienting the critical binding sites.

3)Drug-Receptor Interaction:

A Drug may act as:

1. Agonists bind to the receptor and have the same effect as the substance that

normally binds to the receptor, such as heroin or oxycodone. Inverse agonists, like

competitive antagonists, stabilise the receptor in its inactive conformation.

2. Antagonists are substances that, upon binding to the receptor, prevent it from

producing any response, such as naltrexone. Reversible antagonists easily

dissociate from their receptors; irreversible antagonists form a stable, permanent,

or nearly permanent chemical bond with their receptors.

Recent Trends in Drug Design and Discovery:

1. Personalised Medicine is a tailored approach to drug development that allows

medications and dosing to be finely tailored to each patient's genome, environment, and

prognosis, with the benefits of increased efficacy and fewer adverse drug events. These

advantages are available to both post-market patients and clinical trial participants. The

development of trastuzumab for the treatment of breast cancer was an early example of

personalised drug applications. The ability to perform the DNA sequencing required for

this approach allows for more targeted clinical trials.

2. Decentralized Clinical Trials: COVID-19 pandemic and recent advances in digital

technologies, like wearable devices, enabled data to be collected from patients in their

homes or doctor’s offices without no commute and inconveniences of participating

on-site. These factors have resulted in greater patient interest and retention and give

researchers access to a diversified population of participants.

3. Data digitalisation in the pharmaceutical sector: AI is utilized to automate data

processing in order to solve difficult medical problems. AI aids in drug discovery,

retooling, adverse reaction prediction, and clinical trials. It also aids in decision-making

to pick the best therapy for patients. Overall, data-driven intelligent technologies make

drug discovery practices more cost-effective, speedier, and constructive.

4. In-vitro and cell-based assays: Poor assay decisions produce unreliable, inconsistent, or

deceptive, results causing delays and program failure. The advancement of assay

technology aims to increase output and lower attrition rates. Foresee Biosystems, an

Italian start-up provides cardiotoxicity assays to evaluate the negative effects of

medications on patients' hearts. Using in vitro human heart cells, the startup's unique laser
technique scans and analyses the intracellular electrical activity. This non-invasive assay

quickly uncovers hidden patterns of potentially harmful medicines.