Drug design and drug development- Drug design/development

methods and protocols, target identification, bioinformatics and

biological databases
Biomedical Engineering Applications in Drug Development

•Controlled drug delivery systems (e.g., nanoparticles, hydrogels)

•Biomaterial design for sustained release
•Smart drug delivery (stimuli-responsive systems)
―Traditional vaccines take 10–15 years to develop. How did
we get a COVID-19 vaccine approved in less than a year?
Was it a shortcut or a scientific revolution?‖
Traditional Vaccine Development Timeline (10–15 years)
Stage Description Typical Duration
Target identification, animal
Discovery & Preclinical 2–5 years
studies, toxicity testing
Safety and dosage (20–100
Phase I 1–2 years
volunteers)
Efficacy and side effects (several
Phase II 2–3 years
hundred people)
Large-scale trials for efficacy and
Phase III 3–5 years
safety (thousands of people)
Submission to FDA/EMA,
Regulatory Review 1–2 years
approval process
Manufacturing & Scale-Up Begins after approval 1–2 years
Total Time 10–15 years
 COVID-19 Vaccine Development Timeline (2020–2021)

Stage Description & Acceleration Strategy Duration

SARS-CoV-2 genome sequenced in
Discovery & Preclinical January 2020; animal models quickly <3 months
initiated
Safety + immune response tested
Phase I/II Combined April–July 2020 (~3 months)
simultaneously (100s of participants)
Large-scale efficacy (e.g., 30,000+
Phase III participants) started while earlier phases July–Nov 2020 (~4 months)
ran
Regulators reviewed data in real time,
Rolling Regulatory Review Started Oct 2020
not after full submission
Emergency Use Authorization Issued by FDA in Dec 2020 for Pfizer-
Dec 2020
(EUA) BioNTech

Manufacturing Scale-Up
Began during clinical trials using pre-
Mid-2020 onward
agreed government funding
Total time
11 months
Proteins as targets
Transporters
•Neurotransmitter Transporters: Targets in neurological disorders (e.g., serotonin
transporter [SERT], dopamine transporter [DAT]).
•Glucose Transporters: Important in metabolic diseases (e.g., GLUT4).
Structural Proteins
•Tubulin: Target for anticancer drugs like taxanes and vinca alkaloids.
•Actin: Involved in cell motility and stability.

Nucleic Acids
•DNA:
• Direct targeting with intercalating agents (e.g., doxorubicin).
• Inhibition of DNA synthesis with alkylating agents (e.g., cisplatin).
•RNA:
• Antisense oligonucleotides (e.g., nusinersen).
• RNA interference (RNAi)-based drugs (e.g., patisiran).
•MicroRNAs: Emerging targets in cancer and genetic diseases.
Target identification and its role in drug discovery and development
Examples of targets:
Proteins as targets
Enzymes
•Kinases: Key regulators in signaling pathways (e.g., EGFR, JAK).
•Proteases: Involved in protein degradation (e.g., HIV protease, angiotensin-converting enzyme [ACE]).
•Polymerases: Essential for DNA/RNA synthesis (e.g., DNA polymerase, RNA-dependent RNA
polymerase).
•Cyclooxygenases (COX): Targets for anti-inflammatory drugs (e.g., COX-1, COX-2).

Receptors
•G Protein-Coupled Receptors (GPCRs): Largest target class (e.g., β-adrenergic receptors,
opioid receptors).
•Ion Channels: Important in neuronal signaling (e.g., sodium, potassium, calcium channels).
•Nuclear Receptors: Regulate gene expression (e.g., estrogen receptor, glucocorticoid receptor).
•Receptor Tyrosine Kinases (RTKs): Key in cancer therapy (e.g., HER2, VEGFR).
 Lipids as targets
•Membrane Lipids: Targets for antimicrobial agents disrupting membranes (e.g.,
daptomycin).
•Lipid Metabolism Enzymes:
 HMG-CoA reductase for cholesterol lowering (e.g., statins).
 Lipoprotein lipase for metabolic disorders.

Carbohydrates
•Glycosaminoglycans: Heparin for anticoagulation.
•Glycoproteins: Enzymes involved in glycosylation (e.g., fucosyltransferase in cancer).

Cellular Components and Pathways

•Cell Cycle Regulators: CDKs (cyclin-dependent kinases) in cancer
therapy.
•Apoptotic Pathways: BCL-2 family proteins (e.g., venetoclax).
•Immune Checkpoints:
• CTLA-4 and PD-1/PD-L1 pathways for immunotherapy.
• Toll-like receptors (TLRs) for modulating innate immunity.
Microbial and Viral Targets
•Bacterial Targets:
• Cell wall synthesis enzymes (e.g., penicillin-binding proteins).
• Ribosomal subunits (e.g., macrolides, tetracyclines).
• DNA gyrase (e.g., fluoroquinolones).
•Viral Targets:
• Reverse transcriptase (e.g., in HIV).
• Proteins involved in viral entry (e.g., gp41, gp120).
• Capsid proteins and helicases.
Emerging and Novel Targets
•Epigenetic Regulators:
• Histone deacetylases (HDACs).
• DNA methyltransferases (DNMTs).
•Microbiome Components: Bacterial enzymes/metabolites influencing host health.
•Artificial Targets: Engineered receptors (e.g., CAR-T cells).
•Metabolic Pathways: Enzymes in pathways unique to disease states (e.g., glycolysis in
cancer).
 Target Identification:
•Genomics and proteomics for identifying disease-related targets.
•CRISPR/Cas9 gene-editing for target validation.
Methods of target identification
Genomics refers to the study of an organism's entire genetic makeup (its genome). In drug development,
genomics helps identify disease-related genes and mutations that could serve as therapeutic targets. For
example, genetic sequencing can reveal overexpressed genes in cancer or mutations associated with
genetic disorders, enabling researchers to design drugs that specifically target these abnormalities. Tools
like CRISPR-Cas9 are also used to validate genetic targets by studying the effects of gene editing in
disease models.
Example: The most common EGFR mutations that are responsive to gefitinib are exon 19
deletions and the L858R point mutation.
CRISPR-Cas9 is employed to study gene function and validate potential drug targets:
Knockout Studies: By knocking out specific genes, researchers can identify which ones
are critical for disease progression. Deleting oncogenes to confirm their role in cancer is
an example.
Creation of Disease Models
CRISPR-Cas9 is used to create accurate in vitro and in vivo models:
•Animal Models: Precise edits in animal genomes mimic human disease conditions,
enabling the study of disease mechanisms and therapeutic interventions.
Off-Target Effects Studies: CRISPR is used to study drug off-target effects by
systematically disrupting off-target genes.

Therapeutic development: CRISPR-Cas9 can directly correct or disrupt disease-causing

genes, leading to novel therapies. Gene Correction: Fixing mutations responsible for
genetic disorder. Example: Correcting the mutation causing sickle cell anemia
Proteomics, on the other hand, focuses on the study of proteins—the functional products
of genes. Since many diseases result from abnormal protein expression, structure, or
interactions, proteomics allows researchers to identify and characterize proteins involved in
these processes. Advanced techniques like mass spectrometry and protein interaction
mapping are employed to identify druggable proteins, their structures, and their roles in
disease pathways..
Example: HER 2 in breast cancer.
 in vitro ADME and in vivo Pharmacokinetics

Pharmacokinetics is a drug's journey through the body, during which it passes through
four different phases: absorption, distribution, metabolism, and excretion (ADME).

Absorption: Describes how the drug moves from the site of administration to the site of
action.
Distribution: Describes the journey of the drug through the bloodstream to various tissues
of the body.
Metabolism: Describes the process that breaks down the drug.
Excretion: Describes the removal of the drug from the body.

The pharmacokinetic profile of a compound can be defined as what the body does to the
compound. Is the compound readily absorbed in the gastrointestinal (GI) tract?
Compounds that are not absorbed into the body are unlikely to be drugs.
 Influence of solubility, permeability, lipophilicity and excretion on
Pharmakokinetic properties: absorption, distribution, metabolism, and
excretion (ADME)

Issues of physicochemical properties such as solubility, permeability, and lipophilicity and

excretion can also have a major impact on the success of a drug discovery program. In modern
drug discovery research, a wide variety of physicochemical properties are examined in the early
stages of drug discovery.

A study provided evidence that 40% of clinical candidate failures were caused by poor
pharmacokinetic properties.
 ADME and Structural feature of a compound

Excretion by the kidneys removes the compound from the systemic circulation, preventing
it from exerting biological activity. Collectively, these questions address the absorption,
distribution, metabolism, and excretion profile of a compound and are often referred to as a
compound’s in vivo ADME properties.

Understanding these features of a molecule can provide a great deal of insight as to

whether or not a compound will survive the rigors of clinical trials.
Protocols for drug development
 Clinical development (Phase I–III)
 Regulatory review
 Marketing approval
 market launch, and
 Post-marketing development.
The Investigational New Drug Process
Objective: Gain regulatory approval to begin human trials.
Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA/DGDA
before beginning clinical research.
In the IND application, developers must include:
•Animal study data and toxicity (side effects that cause great harm) data
•Manufacturing information
•Clinical protocols (study plans) for studies to be conducted
•Data from any prior human research
•Information about the investigator

Source: [Link]
Approval
The FDA review team has 30 days to review the original IND submission. The process protects volunteers who
participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND
applications in one of two ways:
•Approval to begin clinical trials.
•Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:
• Participants are exposed to unreasonable or significant risk.
• Investigators are not qualified.
• Materials for the volunteer participants are misleading.
• The IND application does not include enough information about the trial’s risks.
A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In
most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the
proposed study.

[Link]
 FDA Post-Market Drug Safety Monitoring

Even though clinical trials provide important information on a drug’s efficacy and safety, it is
impossible to have complete information about the safety of a drug at the time of
approval. Despite the rigorous steps in the process of drug development, limitations
exist. Therefore, the true picture of a product’s safety actually evolves over the
months and even years that make up a product’s lifetime in the marketplace. FDA
reviews reports of problems with prescription and over-the-counter drugs, and can
decide to add cautions to the dosage or usage information, as well as other measures
for more serious issues.
Regulatory Submission and Approval
Objective: Obtain market approval for the drug.
•Submit a New Drug Application (NDA) or Biologic License Application (BLA) to
regulatory agencies, including:
• Results from all preclinical and clinical studies.
• Manufacturing and quality control data.
• Proposed labeling and usage guidelines.

Post-Marketing Surveillance (Phase IV)

Objective: Monitor long-term safety and effectiveness.
•Conduct post-marketing studies to:
• Detect rare or long-term adverse events.
• Study additional indications or patient populations.
What is HTS?

High-Throughput Screening is an automated process that uses robotics, data processing,

and sensitive detection methods to:
•Screen large chemical libraries.
•Identify "hits" — compounds that modulate a biological target (e.g., inhibit an enzyme or
bind a receptor).
 Physical high throughput screening (HTS) method and virtual
high throughput screening
Fortunately, a number of tools and methods have been developed to address the
simple and yet very complex question of identifying a molecular starting point for a
drug discovery program.

Essentially, there are two general methods utilized in modern drug discovery
programs, physical high throughput screening (HTS) method and virtual high
throughput screening methods.
Advantages of high throughput chemistry and high throughput
screening
By the 1980s, most pharmaceutical companies’ compound collections consisted of only a
few thousand compounds acquired through historical projects and screening programs
remained primarily a manual process, heavily dependent on low throughput assays and
animal models. The situation changed, however, over the last two decades of the twentieth
century with the creation of the fields of high throughput chemistry and high throughput
screening.

In the case of high throughput chemistry, also referred to as combinatorial chemistry or

parallel synthesis, have geared towards increasing efficiency. The preparation of small,
drug like compounds on polymer-based material, for example, was first reported by Robert
B.
HTS Workflow:

[Link] Selection: Choose a biological molecule (enzyme, receptor, protein)

implicated in disease.
[Link] Development: Design a miniaturized, robust, reproducible assay
(usually cell-based or biochemical).
[Link] Screening: Use robots to add thousands of compounds to microtiter
plates (96, 384, or 1536 wells).
[Link]: Use automated detectors (fluorescence, luminescence, absorbance) to
measure biological response.
[Link] Identification: Analyze data to find compounds showing desirable activity.
[Link] Validation & Lead Optimization: Confirm hits, test in secondary assays, and
optimize for potency/selectivity.
FIGURE 2.18 The typical in vitro screening assay employs 96 (left), 384 (middle),
or 1536 (right) well plates. As the plates increase in well number (density), the well
volume decreases and reagent requirements drop accordingly. The cost saving
associated with higher density plates can be substantial
 High throughput chemistry and drug-like compound synthesis
The practice of high throughput chemistry transitioned out of peptides and into
druglike space by the early 1990s with the nearly simultaneous disclosure of the
synthesis of arrays of functionalized 1,4-benzodiazepines on solid support by Jona
than A. Ellman73 and S. Hobbs DeWitt (Figure 2.15).

FIGURE 2.15 In 1992, professor Jonathan Ellman and his colleagues demonstrated
that 1,4-benzodiazepine derivatives could be prepared on solid support. The
application of solid phase chemistry to produce analogs of market drugs such as
Valium® (diazepam), Ativan® (lorazepam), and Rivotril® (clonazepam)
demonstrated that drug-like compounds could be prepared in this manner.
Bioinformatics
Definition : Bioinformatics is an interdisciplinary field that combines biology, computer science,
mathematics, and statistics to analyze and interpret biological data.
Key Functions:
Development of computational tools for biological data analysis.
Management and visualization of large-scale datasets (e.g., DNA, RNA, protein sequences).
Focus Areas:
Sequence Analysis: Comparing DNA, RNA, or protein sequences.
Structural Analysis: Predicting 3D structures of biomolecules.
Functional Analysis: Understanding roles in pathways and networks.
Data Integration: Combining genomics, proteomics, and metabolomics data.
Applications: Vital for genomics, drug discovery, personalized medicine, and
evolutionary biology.

This helps in ADMET analysis,Molecular docking also part of Bioinformatics

Software tools
There are a number of software tools for performing common tasks such as searching databases, aligning
sequences, and creating phylogenetic trees. These tools can be utilized appropriately to perform a number of
high level tasks, such as:
 determining the function of a protein;
 creating a 3D homology model of a protein;
 selecting the appropriate sequence to be targeted by an antisense drug;
 selecting an ideal animal model for drug efficacy testing;
 identifying proteins that should be assayed to check for risk of potential drug side effects;
 finding correlations between adverse effects of drugs and usage by selected ethnic groups;
 learning more about the metabolic pathways, evolution, genetics, and epigenetics relevant to a disease.

The most heavily performed function in bioinformatics is a search for other proteins that are similar to a query
sequence. Most often, a newly identified protein is a member of a known family of proteins. Thus, finding
proteins with known functions that are very similar to an unknown pretty reliably indicates the function of the
unknown protein.
Structure-Based Drug Design (SBDD)

•Using the 3D structure of the biological target (often determined through X-ray crystallography or cryo-
EM) to design drugs that fit precisely.
•Computational approaches, such as molecular docking, play a significant role.

Ligand-Based Drug Design (LBDD)

•Designing drugs based on the known activity of similar molecules (ligands) without relying on the
target's structure.
•Relies heavily on quantitative structure-activity relationships (QSAR).
Pharmacophore Modeling
 Principle: Identifies essential features for biological activity.
 Steps:
1. Align active compounds.
2. Extract common features (e.g., H-bond donors/acceptors).
3. Build a pharmacophore model.
4. Screen libraries for matching molecules.
 Tools: Phase (Schrödinger), LigandScout, Discovery Studio.
 Applications: Virtual screening and lead optimization.
 Virtual screening of HIT using computational approach

Pharmacophore based virtual high throughput screening, a method of overlaying and

comparing a compound of interest with potentially millions of compounds to
determine their similarity, and therefore, potential for binding at a macromolecular
target

Comparisons of this type can be automated, scored, and sorted in order to facilitate the
identification of potentially interesting molecules based on their similarity to known
compounds of interest using specific software.
Molecular Similarity and Virtual Screening
 Principle: Structurally similar molecules often share biological activities.
 Steps:
1. Calculate similarity indices (e.g., Tanimoto coefficient).
2. Identify compounds similar to active ligands.
3. Screen compound libraries.
 Tools: Open Babel, ChemAxon, RDKit.
Applications: Discovering potential drug candidates
Machine Learning
• Principle: Uses machine learning to predict ligand properties.
• Steps:
1. Preprocess data (e.g., feature selection).
2. Train machine learning models.
3. Test and validate models.
• Tools: TensorFlow, PyTorch, scikit-learn, KNIME.
• Applications: Predict activity, toxicity, and solubility trends.
________________________________________
Applications in Drug Discovery

Target Identification and Validation:

 Homology models help in understanding the structure and function of
potential drug targets.
 Key binding sites and conformational states can be identified.

Ligand Docking:
 The modeled protein structure is used for virtual screening to predict
how small molecules (ligands) bind to the target.
 Docking studies can identify lead compounds based on their binding
affinities and interaction profiles.
 X-ray crystallography in drug discovery and development
Macromolecular X-ray crystallography and cryo-EM are currently the primary
techniques used to determine the three-dimensional structures of proteins, nucleic
acids, and viruses. Structural information has been critical to drug discovery and
structural bioinformatics.

The integration of artificial intelligence (AI) into X-ray crystallography has

shown great promise in automating and accelerating the analysis of complex
structural data, further improving the efficiency and accuracy of structure
determination.
The current role and evolution of X-ray crystallography in drug
discovery and development
•X-ray crystallography remains the primary source of experimental structural data for drug discovery.
•Validation should be considered a comprehensive principle that should be incorporated at every stage of
the drug discovery process, including target evaluation, sample preparation, diffraction experiment, model
building, refinement, and structure contextualization.
•The critical role of AI in structural biology and drug design lies in its ability to facilitate sophisticated data
analysis, generate predictive models, improve understanding of molecular structures, and optimize the drug
development process.
•Effective and comprehensive data management is critical for solving the reproducibility crisis in life
science.
•Future improvements in crystallization techniques could enable the crystallization of larger and more
complex proteins, expanding the set of possible drug targets.
 X-Ray Crystallography

X-Ray Crystallography helps elucidating the molecular structure of biological targets,

understanding the interaction of the aforementioned targets with biologically relevant
molecules, and increasing the pace at which the science is explored through the
application of robotics, automation, and computer technology. Advances in one of these
overlapping fields often provided support for new discoveries or technological
advancements in related areas.

The growth of X-ray crystallographic knowledge, for example, had a tremendous impact
on the science of molecular modeling and computational chemistry, and both of these
fields relied heavily on advances in computer technology, an area totally outside of drug
discovery, to increase capabilities and capacity.
The limitations and Drawbacks of x-ray crystallography
•Crystalline samples. The requirement for a crystalline sample is one of the most
significant restrictions of x-ray crystallography. ...
•Model building. Model construction is another x-ray crystallography limitation. ...
•Background noise. ...
•Cost and accessibility.
 Homology Model Building

Structure-based drug design techniques is hampered by the lack of a crystal structure

for the target protein. In this instance, the next best options are either building a
homology model of the entire protein or using a 2D NMR structure of the active site
region. Often, these two options are used together. A homology model gives a model
of the entire protein, while a 2D NMR structure is based on limited data points.
However, the 2D NMR analysis of the active site region conserve to verify that the
homology model is reasonable. Homology model building is sometimes referred to as
a knowledge-based technique, or as comparative protein modeling
Steps for Homology Model Building
Step 1: Template Identification
The object of template identification is to find the protein that has a known crystal structure and has a
very high percent identity to the model sequence—in other words, one that is very close in terms of
evolutionary distance. Ideally, the template should be one protein that has a high percent similarity to the
entire unknown sequence, and large regions of similarity along the entire length of the unknown
sequence.
Step 2: Alignment between the
unknown and the template
Step 3: Manual adjustment to alignment

When there are no known sequences with good homology, even piecewise, a threading
algorithm may be used. This algorithm tries multiple alternative folding motifs, and then
checks whether the resulting structure is reasonable in order to determine which of the
marginal fits gives the best end result. Some threading algorithms are very robust in
comparing sequences with gaps and deletions. There are also sequence fingerprint
techniques, which are a very different algorithm but are like threading in that they work
well to align regions of marginal similarity.
 Step 4: Replace template side chains with model side chains

For those residues that are not identical, the template side chains must be replaced
with the appropriate side chain from the model compound. The only difficult part
of this procedure is optimizing the three-dimensional position of the new side
chain. Often, this is done by performing an optimization on a small conformation
search on just the side chain being inserted, while holding the other side chains
around it in a fixed position. Many of the best side chain placement algorithms are
knowledge-based, meaning that they utilize information such as the most common
conformational position for various residues. Replace template side chains with
model side chains.
 Step 5: Adjust model for insertions and deletions
Once the correct residues are in place, their positions must be optimized. In the case where
several residues are deleted from the template structure, an energy minimization may be
sufficient to obtain a reasonable structure. When residues are inserted, relative to the template
structure, it is necessary to perform some form of conformation search to find the best conformer
for the loop. There are a number of good algorithms for doing this conformation search on just
the loop, including, among others, molecular dynamics, grid searchers, tabu searches, and Monte
Carlo searches. The software documentation should be checked to ensure that the method used
will preserve chirality. Some of the simplest Monte Carlo algorithms tend to invert chiral centers
Step 5: Optimization of the model

The geometry of the protein obtained by following the steps up to this point in the procedure is
usually not the optimal geometry. The backbone geometry taken from the template should be close
to the backbone geometry of the unknown, but is probably not identical. When the backbone
geometry is, that in turn may make it necessary to readjust side chain geometries, even changing to
different rotamers.
 Step 7: Model validation
Homology model validation is a critical step to ensure the reliability and accuracy of
the predicted structure. This process typically involves assessing the stereochemical
quality of the model using tools like PROCHECK or MolProbity, which evaluate
parameters such as bond angles, bond lengths, and Ramachandran plot distributions.
Additionally, structural integrity can be examined by calculating the model's energy
profile with programs like ProSA or Verify3D, which compare the model against
experimentally derived structures. Superimposing the model onto the template structure
also helps assess the conservation of key residues and structural motifs. Such validation
ensures the model is suitable for subsequent analyses, such as docking studies or
functional predictions, and increases confidence in its biological relevance.
Properties of Databases:

Various properties of databases:

Database stores data of relevant information: Data may be Nucleotide sequence, Protein sequence,
Protein sequence pattern, Macromolecular 3-D structure, Gene expression data, and metabolic
pathway.

It has facility for data entry and Quality Control:-Scientist deposit data directly, marking and
removing necessary data, Type and degree of error checking, consistency, conflicts, update, etc.

It may be formed of primary or secondary or other databases:

 Primary databases:-"Experimentally results directly into databases.
 Secondary databases:-"Results of analysis of primary databases"

Data files are stored in specific forms:- They may be Flat file, Rational databases (SQL), Objective
oriented databases (CORB,XML).

It may be maintained by Government or Institutions:- Large, Public Institutions (Ex. EMBL

(European molecular Biology Lab), NCBI), Academic group or scientist ,Commercial company etc.
Significance of Biological Database:

It helps to understand molecular mechanism of diseases which better help in treatment,

cure and efficient diagnosis.

It helps to development of personalized medicine to prescribed best suited drug.

It is used in gene therapy for the treatment of genetic diseases by changing the
expression of victim gene/Person gene.

It also helps in drug designing and drug development.

In addition to these it also help in Bioweapon creation, evolutionary studies, Crop

improvement and improving nutritional quality.
 Biological Information: where to find
Databases Software tools Web Address

NCBI–GenBank [Link]
Nucleic
Acid EBI [Link]
Databases
DNA Data Bank of Japan [Link]

NCBI – GenPept [Link]

ExPasy – SwissProt and

Protein [Link]
TrEMBL
Databases
Protein Data Bank [Link]

EBI – SwissProt, TrEMBL, PIR [Link]

 Nucleic Acid and structural Database
The Nucleic Acid Database ([Link] a more recently
created publicly available database, was established in 1992 to provide the scientific
community with access to three dimensional structures of nucleic acids, and contains
over 6300 solved structures as of 2012 Finally, the Cambridge Structural Database
([Link] founded in 1965, focuses on small molecule
crystal structures, and contains structural information on nearly 600,000 small molecules
as of 2012.
Molecular Modeling and Computational Chemistry
Although Heisenberg’s 1925 paper on quantum mechanics is widely considered to be the
first publication in the field of computational chemistry and molecular modeling, it
would take an additional 36 years for the concept of using computers to calculate and
predict chemical properties and interactions to arrive. In 1961, James Hendrickson
calculated the conformational energies of cyclo-heptane using an IBM 709 computer
that was capable of ―8000 additions/subtractions, 4000 multiplications/divisions, or 500
complex functions per second.‖ In essence, he launched the field of molecular modeling
with a computer that had fewer capabilities and less capacity than most cellular
telephones
 Getting the desired sequences . . .
Way 1: Existing DNA sequences from Databases
3 major gateways (Primary databases)

•National Centre for Biotechnology Information (NCBI)

[Link]/
•The European Bioinformatics Institute (EBI)
[Link]/
• DNA Data Bank of Japan
[Link]/
RCSB Protein Data Bank: A Resource for Chemical, Biochemical,
and Structural Explorations of Large and Small Biomolecules

The PDB archive includes structural information with a wide range of quality, due to the many
challenges inherent in the experimental methods, and the nature of the molecule(s) or
complex(es) being studied. Validation reports for all PDB structures determined by X-ray
crystallography.

Researchers, educators, and students use RCSB PDB resources to study the shape and
interactions of biological molecules and their implications in molecular biology, medicine,
biotechnology, and beyond.

It provide access to more than 113,000 entries of natural and designed macromolecules
(proteins, nucleic acids and carbohydrates), more than 84,000 of which are complexed with
small chemical components (solvent molecules, ions, cofactors, inhibitors, and drugs).
Visualisation and manipulation of protein-ligand structures on a desktop computer

One of its products, Benchware 3D Explorer, provides drug discovery scientists

with the ability to visualize and manipulate protein-ligand structures on a
desktop computer. Ligands can be modified within the context of a protein in
order to gain insight into the impact of structural changes on the potential
binding energy of a new proposed ligand.
FIGURE 2.19 Chemo informatics software platforms provide scientist with the ability to
link compound structures to physicochemical properties (e.g., molecular formula,
molecular weight, Topological Polar Surface Area (TPSA), solubility, etc.) and screening
data from multiple sources in a searchable database. Groups of structurally related
compounds can be identified using sub structure searching tools, and multidimensional
analysis of compound associated data can be used to design next generation compounds
with properties consistent with program goals. In this example, a series of compounds are
analyzed using the Dotmatics software suite and three dimensional plot has been created
to compare changes in molecular.