Structural Bioinformatics

Structural Bioinformatics is based on the protein structure-function paradigm

The function of a macromolecule is dictated by its 3D-structure

The challenges for post genomic era towards a systemic understanding of life are:

To obtain the 3D structures of all the proteins encoded in the genomes

To decode their function based on their structure
 Solved 3D structures Growth
Total number of determined 3D structures of proteins is approx. 137478 (January
2018)
 Is Structure Sufficient to Predict Function?
Proteins are not static; to fulfill their function they undergo a wide range of motion and
conformational rearrangements.

The knowledge of a static structure may not be sufficient to understand its biological
function.

An important component of structural bioinformatics is the development of

experimental and computational methods such as molecular dynamics that sheds
light on the dynamic behavior of biological systems.

These methods simulate they way biomolecules behave, specifically recognize each
other, interact and trigger biological events at the molecular level.
Substrate + Protein Substrate Protein
(Drug) (Target) (Drug) + (Target)

Lock and Key Induced Fit

 Drug Design & Discovery

Drugs: Targets:
Natural sources Synthetic sources
 Important Points in Drug Design based on
Bioinformatics

History of Drug/Vaccine development

• Plants or Natural Product
• Plant and Natural products were source for medical substance
• Example: foxglove used to treat congestive heart failure
• Foxglove contain digitalis and cardiotonic glycoside
• Identification of active component
• Accidental Observations
• Penicillin is one good example
• Alexander Fleming observed the effect of mold
• Mold(Penicillium) produce substance penicillin
• Discovery of penicillin lead to large scale screening
• Soil micoorganism were grown and tested
• Streptomycin, neomycin, gentamicin, tetracyclines etc.
 Important Points in Drug Design based on
Bioinformatics

• Chemical Modification of Known Drugs

• Drug improvement by chemical modification
• Pencillin G -> Methicillin; morphine->nalorphine
• Receptor Based drug design
• Receptor is the target (usually a protein)
• Drug molecule binds to cause biological effects
• It is also called lock and key system
• Structure determination of receptor is important
• Ligand-based drug design
• Search a lead compound or active ligand
• Structure of ligand guide the drug design process
 Two pathways to drug discovery / drug design

Structure-based ligand-based
know receptor (target protein), don’t know receptor (often),
don’t known ligands known ligands

?
What will be happy in there?

Protein/ligand interactions Statistical analysis of what

structure/biophysics group(s) are important for
docking biological activity
 Bioinformatics

Protein

•Large databases
•Not all can be drug targets
•Opportunity for data mining
techniques
A simple example

Protein

Small molecule
drug
A simple example

Protein

Small molecule
drug

Protein
Protein disabled …
disease cured
 Important Points in Drug Design based on
Bioinformatics

Application of Genome
• 3 billion bases pair
• 25,000 unique genes
• Any protein encoded by a gene may be a potential drug
target
• There may be 10 to 100 variants for each target gene
• 1.4 million SNP
• 10200 potential small molecules
 Important Points in Drug Design based on
Bioinformatics
• Identify target disease and refinement of the ligand (drug)
structures

• Detect the Molecular Bases for Disease

• Detection of drug binding site
• Screen likely drug compounds
• Tailor drug to bind at that site: Modeling large
number of compounds
• Protein modeling techniques
• Application of Artificial intelligence
High-Throughput Screening

Screening perhaps millions of compounds in a corporate

collection to see if any show activity against a certain disease
protein
 High-Throughput Screening

• Drug companies now have millions of samples of chemical

compounds

• High-throughput screening can test 100,000 compounds a day for

activity against a protein target

• Maybe tens of thousands of these compounds will show some

activity for the protein

• The chemist needs to intelligently select the 2 - 3 classes of

compounds that show the most promise for being drugs to follow-
up
Target identification in drug discovery
https://youtu.be/1ahQfIT7g48
Molecular Modeling

• 3D Visualization of interactions between compounds and proteins

• “Docking” compounds into proteins computationally
“Docking” compounds into proteins
computationally
 Calculating interaction score between protein and drug: Mixed
Quantum-Classical in a complex environment

Main idea
Partitioning the system into Classical MM

1. Chemical active part interface

treated by QM methods
QM
2. Interface region

3. large environment that is

modeled by a classical
force field
Drug Discovery & Development

Identify disease Drug Design

- Molecular Modeling
- Virtual Screening
Find a drug effective
against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)

Preclinical testing Human clinical trials

D
(1-3 years)

IN
(2-10 years)

le
Fi

A
Formulation

ND
le
Fi
FDA approval
(2-3 years)
 Technology is impacting this process
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and “personalized” targets

HIGH THROUGHPUT SCREENING

Identify disease Screening up to 100,000 compounds a
day for activity against a target protein
VIRTUAL SCREENING
Using a computer to
Isolate protein predict activity

COMBINATORIAL CHEMISTRY
Rapidly producing vast numbers Find drug
of compounds
MOLECULAR MODELING
Computer graphics & models help improve activity
Preclinical testing
IN VITRO & IN SILICO ADMET MODELS
Tissue and computer models begin to replace animal testing
The benefits of using modeling and simulation in drug development
https://youtu.be/o2ntCRCgpUM
 Bioinformatics Implications

• Need to be able to store chemical structure and biological data for millions of
data points
• Computational representation of 2D structure

• Need to be able to organize thousands of active compounds into meaningful

groups
• Group similar structures together and relate to activity

• Need to learn as much information as possible from the data (data mining and
machine learning)
• Apply statistical methods to the structures and related information
 Computational Models of Activity
• Machine Learning Methods
• E.g. Neural networks and SVMs
• Train with compounds of known activity
• Predict activity of “unknown” compounds

• Scoring methods
• Profile compounds based on properties related to target

• Fast Docking
• Rapidly “dock” 3D representations of molecules into 3D
representations of proteins, and score according to how well they
bind
In-vitro & in-silico ADMET models

• Traditionally, animals were used for pre-human testing.

However, animal tests are expensive, time consuming and
ethically undesirable

• ADMET (Absorption, Distribution, Metabolism, Excretion,

Toxicity) techniques help model how the drug will likely act in
the body

• These methods can be experimental (in vitro) using cellular

tissue, or in-silico, using computational models
 In-silico ADMET Models
• Computational methods can predict compound properties
important to ADMET, e.g.

• LogP, a lipophilicity/hydrophobicity measure

• Solubility
• Permeability
• Cytochrome p450 metabolism

• Means estimates can be made for millions of compounds,

helping reduce “attrition” – the failure rate of compounds in
late stage
The benefits of using Pharmacokinetic and Pharmacodynamic modeling
https://youtu.be/jxvJHXVIV4E
Permeability issues: The Blood-Brain Barrier
The role and importance of the blood-brain barrier
https://youtu.be/gCXso3bcEXI
 The most favorite target of Drugs: G-protein-coupled
receptors (GPCR)
GPCRs are involved in virtually every physiological process you can think of, from
sensing colors, flavors and smells to the action of neurotransmitters and hormones

Schematic representation of a few representative GPCRs embedded in the cell

membrane.
 Pharmaceutical relevance

Membrane proteins are crucial for survival:

•Key components for cell-cell signaling

•Mediate the transport of ions and solutes across the membrane

•Crucial for recognition of self.

•The pharmaceutical industry preferably targets membrane-bound receptors.

•Receptors for hormones, neurotransmitters, growth factors, light and

odor-related ligands

•More than 50% of the prescription drugs act on GPCRs.

Current estimation ~1000 GPCRs in human genome

Overview of Signal Transduction by GPCRs
Overview of Signal Transduction by GPCRs: Mechanism
Role and importance of GPCRs in drug discovery
https://youtu.be/3lcoweP_z4M
Success of computer aided drug discovery:

Some of the earliest examples of approved drugs that owe their

discovery in large part to the tools of CADD include the following:

carbonic anhydrase inhibitor dorzolamide used to treat glaucoma

(Vijayakrishnan 2009)

the angiotensin-converting enzyme (ACE) inhibitor, captopril, an

antihypertensive drug (Talele et al., 2010)

three therapeutics for the treatment of human immunodeficiency

virus (HIV): saquinavir, ritonavir, and indinavir (Van Drie 2007)

tirofiban, decrease platelet aggregation (Hartman et al., 1992)