MOLECULAR MODELING AND DRUG DESIGNING

STRCUTURE BASED DRUG DESIGN

M.THILAKAR,

LS1154,

4’th M.Sc. LIFE SCIENCES,

BDU,

TRICHY.

ROAD TO NEW DRUGS

BASIC STUDIES PRECLINICAL

TRIAL

CLINICAL TRAIL

REGISTRATION

1-4 YEARS 5-6 YEARS 6-12.5YEARS

12.5-14YEARS

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ROAD TO NEW DRUGS

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STRUCTUAL BIOINFORMATICS

Structural bioinformatics can facilitate the discovery, design, andoptimization of new chemical entities.

Range from : Drugs and Biological probes to biomaterials, catalysts, andnew macromolecules.

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 optimumsolution to the many different challenges involved in designing materialswith new properties

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STARTING A STRUCTURE-BASED DRUG DISCOVERY PROJECT –GENERAL CONSIDERATIONS

Starts with target identification and verification to obtain a “verified drugtarget”.

For structure-based drug design the three-dimensional structure of theprotein needs to be determined.

When identifying a drug target, we first need to answer some generalquestions:

DRUG TARGET..??

Does the target protein

belong to a biochemical

pathway

If our aim is to inhibit a

protein belongs to a

pathogen, Are there any

related proteins in the

human host

If the protein is not so

well studied one could

also ask if it is actually

drugable.?

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WHY TARGET IDENTIFICATIONS..????

Helps in mapping available interactions within the active site,

which in turn will help in the next step when new compounds will bedesigned.

If there is no three-dimensional structure available for the protein targetone 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 andanalysis may easily answer questions related to the specificity of a particulartarget in a given organism.

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STRUCTURE-BASED DESIGN

The first step in structure based drug design is the determination of the 3Dstructure of the target macromolecule,

Primarily by X-ray crystallography and NMR spectroscopy or computationalmethods such as homology modeling or ab-initio methods

The negative image of the receptor defines the space available for ligandbinding.

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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SOURCE :

Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig 3/19/2015 LS1154 - M. THILAKAR 9

SITE-DIRECTED LIGAND GENERATION

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 ormolecular 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 notlimited to previously synthesized compounds .

SITE-DIRECTED

LIGAND

GENERATION

DOCKING

BUILDING

(DE NOVO DESIGN)

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DOCKING

The aim of molecular docking is to evaluate the feasible bindinggenome tries of a putative ligand with a target whose 3Dstructure is known.

The binding geometries, often called binding modes or posesinclude both the positioning of the ligand relative to the receptor(ligand configuration) and the conformational state(s) of theligand and the receptor.

Docking methods can therefore be evaluated by their ability torapidly and accurately dock large numbers of small moleculesinto the binding site of a receptor, allowing for a rank orderingin 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 ofbinding.

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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(“scoring”).

In order to screen large databases, automated docking is required.

GEOMETRIC SEARCH METHODS : Include systematic search grids as well as descriptormatching.

ENERGY SEARCH METHODS : Include accomplishes the alignment of the ligands byminimizing the ligand-receptor interaction energy using Monte Carlo or moleculardynamics simulations or genetic algorithms

AUTOMATED

SEARCHING METHODS

GEOMETRIC SEARCH

METHOD

ENERGY SEARCH

METHOD

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VIRTUAL LIBRARY DESIGN

The advent of combinatorial chemistry has stimulated the development ofcomputational screening of libraries of compounds that, themselves, mighteither be real or assembled on the computer.

It is possible to make many more compounds computationally than can besynthesized or screened experimentally.

Virtual screening and the use of library design principles are thus beingused to prioritize experimental efforts to make the best use of chemical andscreening resources.

The advantage of virtual screening over random high-throughputscreening is the generation of directed libraries considering molecularproperties that meet criteria required for drug-likeness ADME and exhibitspecificity for the selected target.

The limiting aspect in designing virtual libraries is the syntheticaccessibility of the products by combinatorial library synthesis techniques.3/19/2015 LS1154 - M. THILAKAR 14

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SOURCE :STRUCTURAL BIOINFORMATICS EDITED BY PHILIP E BOURNE AND

HELGE WEISSIG

DE-NOVO

DESIGN The central concept of de novodesign is the construction ofmolecules that have notnecessarily been synthesizedpreviously.

There are three basic classes ofde novo design methods:

Fragment-positioning methods,

Fragment-connecting methods,and

Sequential-grow methods.

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1. FRAGMENT PLACEMENT

Instead of completely building up a new ligand, these methodsdetermine favorable binding positions for single atoms or smallfragments (GRID [Goodford, 1985]; MCSS [Miranker and Karplus, 1991.

The underlying assumption is that a small number of well-placedfragments will account for significant binding interaction, while therest of the molecule serves as a scaffold that links active fragmentstogether.

The fragments are chosen to capture the basic molecular interactionssuch as hydrogen bonding (donor/acceptor) and hydrophobicity, and tooptimally represent the functional groups and structural subunitspresent in a larger diverse library.

The placement procedure uses either a molecular mechanics forcefield or a rule-based approach derived from an analysis of structuraldatabases.

Both the fragment connection method and the anchor-and-growapproach rely on a set of previously placed fragments as starting

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2. CONNECTION METHODS

Site point connection methods attempt to place small molecules in thebinding pocket to match site points that provide favorable interactions.

The site points are either derived directly by rules or by previousfragment placement, as described in fragment placement.

Fragment connection methods retrieve scaffolds from a database inorder to connect isolated fragments by overlaying corresponding bondvectors.

A suitable linker (rigid or flexible) provides a compatible geometryfor connecting the critical fragments.

In a final step, the linker has to be tested for overlap with thereceptor.

The large number of available programs using connection strategiesreflects the fact that molecular fragments are a standard tool ofchemists.3/19/2015 LS1154 - M. THILAKAR 18

3. SEQUENTIAL GROW

The step-by-step construction of ligand within a binding pocket is anotheruseful approach for generating new potential leads or optimizing thefunctionality of a known inhibitor.

First, a seed atom or fragment is placed in the binding site and then the newligand is successively built up by bonding additional structural elements.

Flexibility is introduced by conformational searching and minimization or byrandom orientations accepted by Monte Carlo criteria.

The building procedure is guided by scoring the growing ligand at eachstep.

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, smallerbinding ligands are generated compared to fragment joining methods.

Another, less obvious, difficulty is the vastness of chemical space comparedwith the (relatively) small number of compounds that are feasible from thestandpoint of synthetic chemistry (Clark, Murray, and Li, 1997).

An extension to the sequential-grow procedures is the

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LIMITATIONS

All the de novo methods face a common set of problems.

Since the overall shape of the generated compounds is imposed by thebinding site, it is not guaranteed that the generated conformations of theligands are energetically optimal.

Point charges (used in force fields) are constantly changing during thebuilding process.

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

LIGAND-BASED

(ANALOG-BASED) DESIGN

> Relies on a set of known ligands and is

particularly valuable

If no structural information about the receptor is

available.

> Hence, it is generally applicable to all classes of

drugs.

TARGET-BASED

(RECEPTOR-BASED) DESIGN

> Usually starts with the structure of a receptor

site.

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

modeling.

(Al-Lazikani et al., 2001).

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LIGAND-BASED DESIGN

Based on the known Ligands and their structural activity.

It is necessary to have experimental affinities and molecular propertiesof a set of active compounds, for which the chemical structures areknown.

ANALOG BASED DRUG

DESIGN

PHARMACOPHORE

MAPS

QUANTITATIVE

STRUCTURE-ACTIVITY

RELATIONSHIPS (QSAR)

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LIGAND-BASED DRUG DESIGNVIRTUAL

SCREENING

•2D, 3D and QSAR

method.DE NOVO DRUG

DESIGN

• MODELS :

Simulations and

Knowledge based

modelling

• CONSTRUCTION OF

ALGORITHMS : Incremental

construction, Fragment based

and Stochastic optimization

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2D STRUCTURE MATCHING

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2D SUB - STRUCTURE MATCHING

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3D STRUCTURE MATCHING

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FRONT PAGE OF MOLECULAR

ENVIRONMENT3/19/2015 LS1154 - M. THILAKAR 29

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IDENTIFYING THE TARGET AND DOCKING

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HOW TO DRAW DRUG IN CHEMDRAW

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DOCKING WITH OUR NEW DRUG

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LIGAND INTERACTIONS

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REFERENCES

Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig Pg :441-497

Structure-Based Drug Design: Docking and Scoring by Romano T. KroemerCurrent Protein and Peptide Science, 2007, 8, 312-328

Virtual screening and molecular docking by Dr. Sander B Nabruus, Centre forMolecular and Biomolecular informatics, Radboud university.

Introduction to structure based drug design - A practical guide by Taraphillips, Christophe lmj verlinde and Wim Gj HOL Structure 15 July1994, 2:577-587.

Structure-Based Drug Design By Thomas Funkhouser, Princeton UniversityCS597A, Fall 2005

From laptop to benchtop to bedside: Structure-based Drug Design onProtein Targets Lu Chen et al., Curr Pharm Des . 2012 ; 18(9): 1217–1239.

http://www.proteinstructures.com/SBDD/structure-drug.html

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