2D STURCTURE USES (PREVIOUSLY) * Does the target protein belong to a biochemical pathway, which can be bypassed by the cell, if inhibited? Obviously, if the pathway can be bypassed, inhibiting it will not make much difference. If our aim is to inhibit a protein belongs to a pathogen, Are there any related proteins in the human host, which may be affected by the drug? If the protein is not so well studied one could also ask if it is actually drugable.? In the sense that it has a small-molecule binding site for which a binding compound can be designed.
LIGAND : A molecule (of any size) that binds or interacts with another molecule through non-covalent forces (chemical bond formation) TARGET or receptor is typically the larger species. There are many physical, chemical, and biological properties of the complex that will be influenced by changes in the ligand. The nature of the interaction between ligand and receptor depends on a balance in the chemical/physical forces between them and the forces between each of these molecules and the solvent or environment. These forces basically arise from the interaction of electrons and are studied at the most fundamental level using quantum mechanics (QM). However, the direct application of quantum theory to molecules of biological interest remains limited by computational resources for systems larger than a few amino acids.
PHARMACOPHORE : An explicit geometric hypothesis of the critical features of a ligand.
Functional groups of the leads, it is necessary to specify the individual compounds bound state.
Hydrogen-bond donors and acceptors, charged groups, and hydrophobic patterns.
** QSAR : The goal of QSAR studies is to predict the activity of new compounds based solely on their chemical structure.
The underlying assumption is that the biological activity can be attributed to incremental contributions of the molecular fragments, determining the biological activity. This assumption is called the linear free energy principle.
The predictive nature of a QSAR approach is limited to new compounds that are similar to the compounds from the training set. There is also a risk of chance correlations.
STRUCTURE BASED DRUG DESIGN - MOLECULAR MODELLING AND DRUG DISCOVERY
MOLECULAR MODELING AND
STRCUTURE BASED DRUG
4’th M.Sc. LIFE
ROAD TO NEW DRUGS
BASIC STUDIES PRE
1-4 YEARS 5-6 YEARS 6-12.5
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ROAD TO NEW DRUGS
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Structural bioinformatics can facilitate the discovery, design, and
optimization of new chemical entities.
Range from : Drugs and Biological probes to biomaterials, catalysts, and
Molecular design is important in fields as diverse as organic chemistry,
physical chemistry, chemical engineering, chemical physics, bioengineering,
and molecular biology.
No single strategy or method has come forward that provides an optimum
solution to the many different challenges involved in designing materials
with new properties
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STARTING A STRUCTURE-BASED
DRUG DISCOVERY PROJECT –
Starts with target identification and verification to obtain a “verified drug
For structure-based drug design the three-dimensional structure of the
protein needs to be determined.
When identifying a drug target, we first need to answer some general
Does the target protein
belong to a biochemical
If our aim is to inhibit a
protein belongs to a
pathogen, Are there any
related proteins in the
If the protein is not so
well studied one could
also ask if it is actually
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Helps in mapping available interactions within the active site,
which in turn will help in the next step when new compounds will be
If there is no three-dimensional structure available for the protein target
one could try to find a structure of a homologous protein,
which may subsequently be used for homology modeling.
A search of sequence databases followed by sequence alignment and
analysis may easily answer questions related to the specificity of a particular
target in a given organism.
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The first step in structure based drug design is the determination of the 3D
structure of the target macromolecule,
Primarily by X-ray crystallography and NMR spectroscopy or computational
methods such as homology modeling or ab-initio methods
The negative image of the receptor defines the space available for ligand
There may be many potential binding sites.
The actual binding site can be located by comparison with known protein–
ligand complexes or through homology to related complexes.
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Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig
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Site-directed ligand generation branches into two main approaches:
Docking methods search available databases for matches to an active site,
whereas de novo design seeks to generate new ligands by connecting atoms or
molecular fragments uniquely chosen for a particular receptor.
Docking is the computational equivalent of high-throughput screening.
De novo design can suggest chemically novel ligand classes that are not
limited to previously synthesized compounds .
(DE NOVO DESIGN)
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The aim of molecular docking is to evaluate the feasible binding
genome tries of a putative ligand with a target whose 3D
structure is known.
The binding geometries, often called binding modes or poses
include both the positioning of the ligand relative to the receptor
(ligand configuration) and the conformational state(s) of the
ligand and the receptor.
Docking methods can therefore be evaluated by their ability to
rapidly and accurately dock large numbers of small molecules
into the binding site of a receptor, allowing for a rank ordering
in terms of strength of interaction with a particular receptor.
Therefore, the essential feature of any treatment of ligand-
receptor interaction is the correct estimation of free energy of
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TASKS OF DOCKING
There are three basic tasks any docking procedure must accomplish:
(1) Characterization of the binding site;
(2) Positioning of the ligand into the binding site (orienting); and
(3) Evaluating the strength of interaction for a specific ligand-receptor complex
In order to screen large databases, automated docking is required.
GEOMETRIC SEARCH METHODS : Include systematic search grids as well as descriptor
ENERGY SEARCH METHODS : Include accomplishes the alignment of the ligands by
minimizing the ligand-receptor interaction energy using Monte Carlo or molecular
dynamics simulations or genetic algorithms
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VIRTUAL LIBRARY DESIGN
The advent of combinatorial chemistry has stimulated the development of
computational screening of libraries of compounds that, themselves, might
either be real or assembled on the computer.
It is possible to make many more compounds computationally than can be
synthesized or screened experimentally.
Virtual screening and the use of library design principles are thus being
used to prioritize experimental efforts to make the best use of chemical and
The advantage of virtual screening over random high-throughput
screening is the generation of directed libraries considering molecular
properties that meet criteria required for drug-likeness ADME and exhibit
specificity for the selected target.
The limiting aspect in designing virtual libraries is the synthetic
accessibility of the products by combinatorial library synthesis techniques.3/19/2015 LS1154 - M. THILAKAR 14
STRUCTURAL BIOINFORMATICS EDITED BY PHILIP E BOURNE AND
The central concept of de novo
design is the construction of
molecules that have not
necessarily been synthesized
There are three basic classes of
de novo design methods:
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1. FRAGMENT PLACEMENT
Instead of completely building up a new ligand, these methods
determine favorable binding positions for single atoms or small
fragments (GRID [Goodford, 1985]; MCSS [Miranker and Karplus, 1991.
The underlying assumption is that a small number of well-placed
fragments will account for significant binding interaction, while the
rest of the molecule serves as a scaffold that links active fragments
The fragments are chosen to capture the basic molecular interactions
such as hydrogen bonding (donor/acceptor) and hydrophobicity, and to
optimally represent the functional groups and structural subunits
present in a larger diverse library.
The placement procedure uses either a molecular mechanics force
field or a rule-based approach derived from an analysis of structural
Both the fragment connection method and the anchor-and-grow
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2. CONNECTION METHODS
Site point connection methods attempt to place small molecules in the
binding pocket to match site points that provide favorable interactions.
The site points are either derived directly by rules or by previous
fragment placement, as described in fragment placement.
Fragment connection methods retrieve scaffolds from a database in
order to connect isolated fragments by overlaying corresponding bond
A suitable linker (rigid or flexible) provides a compatible geometry
for connecting the critical fragments.
In a final step, the linker has to be tested for overlap with the
The large number of available programs using connection strategies
reflects the fact that molecular fragments are a standard tool of
chemists.3/19/2015 LS1154 - M. THILAKAR 18
3. SEQUENTIAL GROW
The step-by-step construction of ligand within a binding pocket is another
useful approach for generating new potential leads or optimizing the
functionality of a known inhibitor.
First, a seed atom or fragment is placed in the binding site and then the new
ligand is successively built up by bonding additional structural elements.
Flexibility is introduced by conformational searching and minimization or by
random orientations accepted by Monte Carlo criteria.
The building procedure is guided by scoring the growing ligand at each
The final results often depend on the selection of the initial position.
Since the selection of each added unit is based on its binding score, smaller
binding ligands are generated compared to fragment joining methods.
Another, less obvious, difficulty is the vastness of chemical space compared
with the (relatively) small number of compounds that are feasible from the
standpoint of synthetic chemistry (Clark, Murray, and Li, 1997).3/19/2015 LS1154 - M. THILAKAR 19
All the de novo methods face a common set of problems.
Since the overall shape of the generated compounds is imposed by the
binding site, it is not guaranteed that the generated conformations of the
ligands are energetically optimal.
Point charges (used in force fields) are constantly changing during the
Also, as noted the synthetic accessibility has to be addressed.
Linking methods have not yet been thoroughly explored.
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COMPUTER-AIDED DRUG DESIGN
CADD – STRUCTUR BASED DRUG DESIGN
> Relies on a set of known ligands and is
If no structural information about the receptor is
> Hence, it is generally applicable to all classes of
> Usually starts with the structure of a receptor
Such as the active site in a protein
> This structure can be generated from direct
experimentation or can be deduced from
experimental structures through homology
(Al-Lazikani et al., 2001).
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Based on the known Ligands and their structural activity.
It is necessary to have experimental affinities and molecular properties
of a set of active compounds, for which the chemical structures are
ANALOG BASED DRUG
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•2D, 3D and QSAR
DE NOVO DRUG
• MODELS :
• CONSTRUCTION OF
ALGORITHMS : Incremental3/19/2015 LS1154 - M. THILAKAR 24
2D STRUCTURE MATCHING
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2D SUB - STRUCTURE MATCHING
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3D STRUCTURE MATCHING
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Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig Pg :
Structure-Based Drug Design: Docking and Scoring by Romano T. Kroemer
Current Protein and Peptide Science, 2007, 8, 312-328
Virtual screening and molecular docking by Dr. Sander B Nabruus, Centre for
Molecular and Biomolecular informatics, Radboud university.
Introduction to structure based drug design - A practical guide by Tara
phillips, Christophe lmj verlinde and Wim Gj HOL Structure 15 July
Structure-Based Drug Design By Thomas Funkhouser, Princeton University
CS597A, Fall 2005
From laptop to benchtop to bedside: Structure-based Drug Design on
Protein Targets Lu Chen et al., Curr Pharm Des . 2012 ; 18(9): 1217–1239.
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