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05/03/2023 1
HOMOLOGY MODELING AND MOLECULAR DOCKING: TOOLS FOR
DRUG DISCOVERY
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What is Bioinformatics
• Science that uses the instruments of informatics to analyze biological data in order to formulate hypothesis about life
• 1990s term started appearing in scientific journals
• 1960s onwards laboratories were able to use computers with good graphical performance
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Storage, retrieval and analysis of biological data with informatics tools
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Central Dogma of Life
StructuralFunctional: Catalyst & TransportSignalingImmunityToxins
Disease and Therapy
Functions of Proteins
FLOW OF INFORMATION
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Role in current research????To know how cellular activities are
altered in different disease states
Combining biological data to form a comprehensive picture of these
activities
POSTGENOMIC ERA- learned how to interpret and manipulate a genome.
A wonderful but also worrisome achievement
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Drug Discovery & DevelopmentIdentify disease
Isolate proteininvolved in disease (2-5 years)
Find a drug effectiveagainst disease protein(2-5 years)
Preclinical testing(1-3 years)
Formulation &Scale-up
Human clinical trials(2-10 years)
FDA approval(2-3 years)
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NDA
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Impact of new technology on drug discovery
• The last few years have seen a number of “revolutionary” new technologies:– Gene chips, genomics and HGP– Bioinformatics & Molecular biology– More protein structures– High-throughput screening & assays– Virtual screening and library design– Docking– Combinatorial chemistry– In-vitro ADME testing– Other computational methods
Identify disease
Isolate protein
Find drug
Preclinical testing
GENOMICS, PROTEOMICS & BIOPHARM.
HIGH THROUGHPUT SCREENING
MOLECULAR MODELING
VIRTUAL SCREENING
COMBINATORIAL CHEMISTRY
IN VITRO & IN SILICO ADME MODELS
Potentially producing many more targetsand “personalized” targets
Screening up to 100,000 compounds aday for activity against a target protein
Using a computer topredict activity
Rapidly producing vast numbersof compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing9
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R&D spending up, new drugs down
Source: http://bio-associate.blogspot.in/2013/02/forget-in-house-r-enter-fully.html
To overcome these limitations R&D industry/Academia usingHomology Modeling and Docking tools
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HOMOLOGY
existence of shared ancestry between a pair of structures or genes, in different species
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Determining Structure
• NMR
• X-ray diffraction
• Electron Microscopy
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Why we need a Model???• If the structure of target protein has not been
experimentally determined!!!• One can try to build a model of the protein of interest• Evolutionarily related proteins have similar sequences
and naturally occurring homologous proteins have similar protein structure.
• 3D protein structure is more conserved than would be expected on the basis of sequence conservation alone.
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How to Model
MO
DEL
ING HOMOLOGY
THREADING
ab initio
Based on similar sequence
Based on known folds
From scrap: prop of aa
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Homology ModelingFASTA
sequence
Template search
&selection
Sequence alignment
Model building
Evaluation and
Validation
Modeler, SWISS-Modeler(Dills HP /Cubic lattice model)
QueryTemplate
PROCHECK, VERIFY-3D(Ramachandran plot)RMSD values
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Flow Chart
Structure is the ability to function
“Anifensen theory”
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Sequences vs Structure
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DOCKING
Docking attempts to find the “best” matching between two molecules
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Molecular Docking• Aim of docking:
Whether the two molecules “interact”If so, what is the orientation that maximizes the
“interaction” while minimizing the total “energy” of the complex• ImportanceSignal transductiondrug design: The results of docking can be used to find inhibitors for specific target proteins and thus to design new drugs.
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Types of Docking• Protein-Protein Docking-rigid • Protein-Ligand Docking-flexibleTechniques• Surface representation, that efficiently represents the
docking surface and identifies the regions of interest (cavities and protrusions)
• Connolly surface – atomic sphere• Lenhoff technique- complementary surface• Kuntz et al.,- clusteredSpheres• Alpha shapes- shape
• Surface matching that matches surfaces to optimize a binding score:
• Geometric Hashing
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Docking tools
• GlideDOCK• FlexX• GOLD• AutoDOCK• RosettaDock• Hammerhead • FLOG
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My Recent work @ NIPGR: INSA fellowship
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Model
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Screen shot showing the protein preparation wizard
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Ramachandran plot showing the distribution of residues
Superimposition of iNOS (grey) with final prepared protein (Spectrum)
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Grid generation and Active site identification
Information generated at different points in the Drug Design process
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NDA
Gene chip experiments
Project selection decisionsAssay protocols
HTS resultsSeries selection decisionsSAR studies
Protein structures
Combinatorial Expts.PharmacophoresADME studies
Toxicology studiesScaleup reactions
Lead cmpd decisions
Clinical Trials dataDoctor/patient studies
Marketing, surveys, etc27
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Venkatraman Ramakrishnan
Wide scope for research
structure and function of the ribosome-2009
Roger D. Kornberg
molecular basis of eukaryotic transcription2006
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Important Data Banks and References
http://www.ncbi.nlm.nih.gov/
http://www.rcsb.org/pdb/home/home.do
http://www.uniprot.org/
Pymol
OERS