Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
MOLECULAR MODELING AND
DRUG DESIGNING
STRCUTURE BASED DRUG
DESIGN
M.THILAKAR,
LS1154,
4’th M.Sc. LIFE
SCIENCES,
BDU,
TRICH...
ROAD TO NEW DRUGS
BASIC STUDIES PRE
CLINICAL
TRIAL
CLINICA
L TRAIL
REGISTRATIO
N
1-4 YEARS 5-6 YEARS 6-12.5
YEARS
12.5-14
...
ROAD TO NEW DRUGS
3/19/2015 LS1154 - M. THILAKAR 3
STRUCTUAL
BIOINFORMATICS
Structural bioinformatics can facilitate the discovery, design, and
optimization of new chemical...
STARTING A STRUCTURE-BASED
DRUG DISCOVERY PROJECT –
GENERAL CONSIDERATIONS
Starts with target identification and verifica...
WHY TARGET
IDENTIFICATIONS..????
Helps in mapping available interactions within the active site,
which in turn will help...
3/19/2015 LS1154 - M. THILAKAR 7
STRUCTURE-BASED DESIGN
The first step in structure based drug design is the determination of the 3D
structure of the targ...
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 searc...
DOCKING
The aim of molecular docking is to evaluate the feasible binding
genome tries of a putative ligand with a target ...
TASKS OF DOCKING
There are three basic tasks any docking procedure must accomplish:
(1) Characterization of the binding ...
3/19/2015 LS1154 - M. THILAKAR 13
VIRTUAL LIBRARY DESIGN
The advent of combinatorial chemistry has stimulated the development of
computational screening of...
3/19/2015 LS1154 - M. THILAKAR 15
SOURCE :
STRUCTURAL BIOINFORMATICS EDITED BY PHILIP E BOURNE AND
HELGE WEISSIG
DE-NOVO
DESIGN
The central concept of de n...
1. FRAGMENT PLACEMENT
Instead of completely building up a new ligand, these methods
determine favorable binding positions...
2. CONNECTION METHODS
Site point connection methods attempt to place small molecules in the
binding pocket to match site ...
3. SEQUENTIAL GROW
The step-by-step construction of ligand within a binding pocket is another
useful approach for generat...
LIMITATIONS
All the de novo methods face a common set of problems.
Since the overall shape of the generated compounds is...
3/19/2015 LS1154 - M. THILAKAR 21
COMPUTER-AIDED DRUG DESIGN
CADD – STRUCTUR BASED DRUG DESIGN
LIGAND-BASED
(ANALOG-BASED) DESIGN
> Relies on a set of known...
LIGAND-BASED DESIGN
Based on the known Ligands and their structural activity.
It is necessary to have experimental affin...
LIGAND-BASED DRUG
DESIGNVIRTUAL
SCREENING
•2D, 3D and QSAR
method.
DE NOVO DRUG
DESIGN
• MODELS :
Simulations and
Knowledg...
2D STRUCTURE MATCHING
3/19/2015 LS1154 - M. THILAKAR 25
2D SUB - STRUCTURE MATCHING
3/19/2015 LS1154 - M. THILAKAR 26
3D STRUCTURE MATCHING
3/19/2015 LS1154 - M. THILAKAR 27
3/19/2015 LS1154 - M. THILAKAR 28
FRONT PAGE OF
MOLECULAR
ENVIRONMENT3/19/2015 LS1154 - M. THILAKAR 29
3/19/2015 LS1154 - M. THILAKAR 30
3/19/2015 LS1154 - M. THILAKAR 31
IDENTIFYING THE TARGET
AND DOCKING
3/19/2015 LS1154 - M. THILAKAR 32
3/19/2015 LS1154 - M. THILAKAR 33
3/19/2015 LS1154 - M. THILAKAR 34
3/19/2015 LS1154 - M. THILAKAR 35
HOW TO DRAW DRUG IN
CHEMDRAW
3/19/2015 LS1154 - M. THILAKAR 36
3/19/2015 LS1154 - M. THILAKAR 37
DOCKING WITH OUR NEW
DRUG
3/19/2015 LS1154 - M. THILAKAR 38
3/19/2015 LS1154 - M. THILAKAR 39
3/19/2015 LS1154 - M. THILAKAR 40
3/19/2015 LS1154 - M. THILAKAR 41
LIGAND INTERACTIONS
3/19/2015 LS1154 - M. THILAKAR 42
3/19/2015 LS1154 - M. THILAKAR 43
3/19/2015 LS1154 - M. THILAKAR 44
3/19/2015 LS1154 - M. THILAKAR 45
3/19/2015 LS1154 - M. THILAKAR 46
3/19/2015 LS1154 - M. THILAKAR 47
REFERENCES
 Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig Pg :
441-497
Structure-Based Drug Desi...
3/19/2015 LS1154 - M. THILAKAR 49
3/19/2015 LS1154 - M. THILAKAR 50
Upcoming SlideShare
Loading in …5
×

STRUCTURE BASED DRUG DESIGN - MOLECULAR MODELLING AND DRUG DISCOVERY

7,838 views

Published on

STRUCTURE BASED DRUG DESIGN - MOLECULAR MODELLING AND DRUG DISCOVERY

Published in: Science
  • Be the first to comment

STRUCTURE BASED DRUG DESIGN - MOLECULAR MODELLING AND DRUG DISCOVERY

  1. 1. MOLECULAR MODELING AND DRUG DESIGNING STRCUTURE BASED DRUG DESIGN M.THILAKAR, LS1154, 4’th M.Sc. LIFE SCIENCES, BDU, TRICHY.
  2. 2. ROAD TO NEW DRUGS BASIC STUDIES PRE CLINICAL TRIAL CLINICA L TRAIL REGISTRATIO N 1-4 YEARS 5-6 YEARS 6-12.5 YEARS 12.5-14 YEARS 3/19/2015 LS1154 - M. THILAKAR 2
  3. 3. ROAD TO NEW DRUGS 3/19/2015 LS1154 - M. THILAKAR 3
  4. 4. STRUCTUAL BIOINFORMATICS Structural bioinformatics can facilitate the discovery, design, and optimization of new chemical entities. Range from : Drugs and Biological probes to biomaterials, catalysts, and new 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 optimum solution to the many different challenges involved in designing materials with new properties 3/19/2015 LS1154 - M. THILAKAR 4
  5. 5. STARTING A STRUCTURE-BASED DRUG DISCOVERY PROJECT – GENERAL CONSIDERATIONS Starts with target identification and verification to obtain a “verified drug target”. 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 questions: 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.? 3/19/2015 LS1154 - M. THILAKAR 5
  6. 6. 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 be designed. 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. 3/19/2015 LS1154 - M. THILAKAR 6
  7. 7. 3/19/2015 LS1154 - M. THILAKAR 7
  8. 8. STRUCTURE-BASED DESIGN 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 binding. 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. 3/19/2015 LS1154 - M. THILAKAR 8
  9. 9. SOURCE : Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig 3/19/2015 LS1154 - M. THILAKAR 9
  10. 10. 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 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 . SITE-DIRECTED LIGAND GENERATION DOCKING BUILDING (DE NOVO DESIGN) 3/19/2015 LS1154 - M. THILAKAR 10
  11. 11. DOCKING 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 binding. 3/19/2015 LS1154 - M. THILAKAR 11
  12. 12. 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 descriptor matching. 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 AUTOMATED SEARCHING METHODS GEOMETRIC SEARCH METHOD ENERGY SEARCH METHOD 3/19/2015 LS1154 - M. THILAKAR 12
  13. 13. 3/19/2015 LS1154 - M. THILAKAR 13
  14. 14. 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 screening resources. 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
  15. 15. 3/19/2015 LS1154 - M. THILAKAR 15
  16. 16. SOURCE : STRUCTURAL BIOINFORMATICS EDITED BY PHILIP E BOURNE AND HELGE WEISSIG DE-NOVO DESIGN The central concept of de novo design is the construction of molecules that have not necessarily been synthesized previously. There are three basic classes of de novo design methods: Fragment-positioning methods, Fragment-connecting methods, and Sequential-grow methods. 3/19/2015 LS1154 - M. THILAKAR 16
  17. 17. 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 together. 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 databases. Both the fragment connection method and the anchor-and-grow 3/19/2015 LS1154 - M. THILAKAR 17
  18. 18. 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 vectors. 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 receptor. 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
  19. 19. 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 step. 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
  20. 20. LIMITATIONS 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 building process. Also, as noted the synthetic accessibility has to be addressed. Linking methods have not yet been thoroughly explored. 3/19/2015 LS1154 - M. THILAKAR 20
  21. 21. 3/19/2015 LS1154 - M. THILAKAR 21
  22. 22. 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). 3/19/2015 LS1154 - M. THILAKAR 22
  23. 23. LIGAND-BASED DESIGN 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 known. ANALOG BASED DRUG DESIGN PHARMACOPHORE MAPS QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSAR) 3/19/2015 LS1154 - M. THILAKAR 23
  24. 24. LIGAND-BASED DRUG DESIGNVIRTUAL SCREENING •2D, 3D and QSAR method. DE NOVO DRUG DESIGN • MODELS : Simulations and Knowledge based modelling • CONSTRUCTION OF ALGORITHMS : Incremental3/19/2015 LS1154 - M. THILAKAR 24
  25. 25. 2D STRUCTURE MATCHING 3/19/2015 LS1154 - M. THILAKAR 25
  26. 26. 2D SUB - STRUCTURE MATCHING 3/19/2015 LS1154 - M. THILAKAR 26
  27. 27. 3D STRUCTURE MATCHING 3/19/2015 LS1154 - M. THILAKAR 27
  28. 28. 3/19/2015 LS1154 - M. THILAKAR 28
  29. 29. FRONT PAGE OF MOLECULAR ENVIRONMENT3/19/2015 LS1154 - M. THILAKAR 29
  30. 30. 3/19/2015 LS1154 - M. THILAKAR 30
  31. 31. 3/19/2015 LS1154 - M. THILAKAR 31
  32. 32. IDENTIFYING THE TARGET AND DOCKING 3/19/2015 LS1154 - M. THILAKAR 32
  33. 33. 3/19/2015 LS1154 - M. THILAKAR 33
  34. 34. 3/19/2015 LS1154 - M. THILAKAR 34
  35. 35. 3/19/2015 LS1154 - M. THILAKAR 35
  36. 36. HOW TO DRAW DRUG IN CHEMDRAW 3/19/2015 LS1154 - M. THILAKAR 36
  37. 37. 3/19/2015 LS1154 - M. THILAKAR 37
  38. 38. DOCKING WITH OUR NEW DRUG 3/19/2015 LS1154 - M. THILAKAR 38
  39. 39. 3/19/2015 LS1154 - M. THILAKAR 39
  40. 40. 3/19/2015 LS1154 - M. THILAKAR 40
  41. 41. 3/19/2015 LS1154 - M. THILAKAR 41
  42. 42. LIGAND INTERACTIONS 3/19/2015 LS1154 - M. THILAKAR 42
  43. 43. 3/19/2015 LS1154 - M. THILAKAR 43
  44. 44. 3/19/2015 LS1154 - M. THILAKAR 44
  45. 45. 3/19/2015 LS1154 - M. THILAKAR 45
  46. 46. 3/19/2015 LS1154 - M. THILAKAR 46
  47. 47. 3/19/2015 LS1154 - M. THILAKAR 47
  48. 48. REFERENCES  Structural Bioinformatics Edited by Philip E Bourne and Helge Weissig Pg : 441-497 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 1994, 2:577-587. 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. http://www.proteinstructures.com/SBDD/structure-drug.html http://publications.nigms.nih.gov/structlife/chapter4.html 3/19/2015 LS1154 - M. THILAKAR 48
  49. 49. 3/19/2015 LS1154 - M. THILAKAR 49
  50. 50. 3/19/2015 LS1154 - M. THILAKAR 50

×