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Chemical Databases in

Biological Research
Girinath G. Pillai, PhD
Nyro Research Foundation
Zastra Innovations

www.zastrain.com & www.nyroindia.org


pillai@nyroindia.org
What to expect?
➤ Chemical Representation
➤ Chemical Databases
➤ Herbal/Natural Compound Databases
➤ Drug Discovery
➤ Drug Development
➤ Drug Design Approach

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A grand challenge for all of us is
how to best incorporate existing knowledge….

Martha S. Head, GSK, in 2009


Representing Chemicals
➤ Trivial name, e.g. Baking Soda, Aspirin, Citric Acid, etc.
Identifies the compound, but gives no (or little) information about
what it consists of

➤ Chemical formula, e.g. C6H12O6.


Specifies the type and quantity of the atoms in the compound, but not
its structure (i.e. how the atoms are connected by bonds)

➤ Systematic name, e.g. 1,2-dibromo-3-chloropropane.

Source:
Identifies the atoms present and how they are connected by bonds.
Abou-Gharbia et al, JMC 2013, dx.doi.org/10.1021/jm401564r
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Digital Representations
➤ How do we communicate structural information between humans and the
computer?
– Line notations, e.g. Wiswesser Line Notation (and later SMILES)

➤ How do we represent the atoms and bonds in a molecule internally in a


computer?
– Atom lookup and connection tables

Trivial name : proline


Systematic names : pyrrolidine‐2‐carboxylic acid

Source:
Abou-Gharbia et al, JMC 2013, dx.doi.org/10.1021/jm401564r
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Chemical - File Formats
➤ .mol
➤ .mol2
➤ .sd / sdf
➤ .pdb
➤ .skc/.cdx/.mrv/…
➤ .smi CCCC

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SMILES
➤ Simplified Molecular-Input Line-Entry System (SMILES)
is a specification in form of a line notation for describing the structure
of chemical species using short ASCII strings
➤ SMILES specification was initiated by David Weininger in the 1980s
➤ .smi is the file format for SMILES
OC(=O)C1CCCN1
➤ SMILES form depends on the choices:
➤ of the bonds chosen to break cycles,
➤ of the starting atom used for the depth-first traversal, and
➤ of the order in which branches are listed when encountered.

➤ There are different variants of SMILES


Source:

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Chemical Format Convertors
➤ OpenBabel
➤ Multiple chemical file formats (+ options) and utility
formats
➤ 2D coordinate generation and depiction (PNG and
SVG)
➤ 3D coordinate generation, forcefield minimisation,
conformer generation
➤ Binary fingerprints (path-based, substructure based) Volunteer effort, an open source success story
and associated “fast search” database – Originally a fork from OpenEye’s OELib in 2001
– Lead is Geoff Hutchison (Uni of Pittsburgh)
➤ Bond perception, aromaticity detection and
– 4 or 5 active developers
atomtyping
➤ Canonical labelling, automorphisms, alignment
➤ Plugin architecture
➤ Several command-line applications, but also a
software library
Source:
Open Babel: An open chemical toolbox, J. Cheminf., 2011, 3, 33.

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2D Chemical Searching
➤ Structure search
➤ Is this structure in the database?

➤ Substructure search
➤ Find all structures that contain the substructure?

➤ Similarity search
➤ Find structures that are similar to this one

Source:

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Chemical Databases
Chemical Databases
➤ NCI and CSD
➤ PubChem - maintains three types of information namely, substance, compound and BioAssays
➤ ZINC - contains 21 million compounds available for virtual screening
➤ ChemIDPlus -
➤ DrugBank - detailed drug (i.e. pharmacological and pharmaceutical) data with drug target
➤ ChEMBL - 1 million bioactive (small drug-like molecules) compounds with 8200 drug targets.
➤ BindingDB - contains 910,836 binding data, for 6,263 protein targets and 378,980 small molecules.
➤ KEGG - integrates genomic, chemical and systemic functional information.
➤ SuperDrug - 2500 3D-structures of active ingredients of essential marketed drugs.
➤ Vendor Databases – eMolecules, MolProt, Enamine

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Chemical Databases

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NCI - CACTUS

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NCI - Aspirin

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NCI – DTP – Order Compounds

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NCI – DTP – Cell Line Screening

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CCDC - CSD

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CCDC – CSD – Access Structures

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CCDC – CSD - Aspirin

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PubChem

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PubChem - Benzaldehyde

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ZINC15

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ZINC15 – intrials data

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ZINC - Benzoyl

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ChemIDPlus

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TOXNET

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TOXNET - Resources

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DrugBank

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DrugBank - Acetaminophen

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ChEMBL

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ChEMBL - Data

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ChEMBL - Dopamine

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Binding DB

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Binding DB - Aspirin

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KEGG Compund DB

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KEGG - Paracetamol

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SuperDrug2

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International Contributions

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HIT – Database

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HIT - Quercetagetin

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Super Natural

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NPACT - DB

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Drug Design Approach
Objectives of Drug Discovery
Hit Drug
➤ Identify chemistries with an Potency
Safety
X
optimal balance of properties Absorption
X

Property 2
Solubility
Metabolic
➤ Quickly identify situations when stability

such a balance is not possible Property 1

Potency
Safety
➤Fail fast, fail cheap
➤Only when confident Absorption

Property 2
➤Avoid missed opportunities Solubility
Metabolic
stability
Source :
M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310 Property 1
No good drug
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Drug Development Process

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Drug Discovery
➤ One way to “discover” drugs

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Increase in the Cost of Medicine!

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CADD - Phases

Drug Discovery
Drug Development

Target Lead Lead


Identification Discovery Optimization
Preclinical
Clinical Trails
Tests
•Bioinformatics
•Reverse •Molecular Docking
Docking •Pharmacophore Modeling
•Pharmacophore •Combinatorial Chemistry
Mapping •Library Design •ADME
•Structure
Prediction
Computer Aided Design
•QSAR
•P450
•Toxicity
•PBPK
•Druggability •Multi Parameter Optimisation Simulations
•Probe Design Source:

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Impact of CADD on Pharma (112+)
➤ Acetyl-CoA carboxylase Inhibitor Nimbus, US
➤ Captopril Capoten®, Bristol Myers-Squibb
➤ Dorzolamide Trusopt®, Merck
➤ Zanamivir Relenza®, Gilead Sciences
➤ Aliskiren Tekturna®, Novartis
➤ Boceprevir Schering-Plough
➤ Nolatrexed dihydrochloride Thymitaq®, Agouron
➤ LY-517717 Lilly/Protherics
➤ Rupintrivir AG7088, Agouron
➤ NVP-AUY922 Novartis
➤ Vemurafenib Plexxikon
➤ Venetoclax AbbVie, Genentech
➤ Erdafitinib Johnson & Johnson
➤ Verubecestat Merck Source:
Abou-Gharbia et al, JMC 2013, dx.doi.org/10.1021/jm401564r
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Nyro Research Foundation – www.nyroindia.org
➤ Internships and Project training with real-time projects
➤ Programming languages, environments and high-
performance computing systems
➤ Third-party software tools
➤ Bootcamps, summer camps, annual conference with
tutorials
➤ Hosts monthly web meetings
➤ Shares information resources, including a blog and other
learning materials
➤ Collaborative research projects
➤ Computing Consultants
➤ 2 Interns per year

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Zastra Innovations
➤ Scientific software providers/training
➤ Computational Biology
➤ Computational Chemistry
➤ Materials Science
➤ Nanotechnology
➤ BioStatistics
➤ Dosage Tolerance/Curve Fitting
➤ Medicinal Chemistry / Cheminformatics

➤ Collaborative research projects


➤ Computing Consultants
➤ 2 Interns per year

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Agree / Disagree?
➤ Participants/Delegates
➤ My mentors, colleagues and students.
➤ Organizers of the seminar

➤ Email : gpillai@zastrain.com
➤ Phone: 94483 67493
➤ Web : www.zastrain.com
➤ Inviting Programmers who can
code QSAR models and web portal

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