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SEMINAR IN BIOPHYSICS

MOLECULAR DOCKING
INTERNAL ASSESSMENT - II

BY
M.GOPINATH
REG.NO: 34117010
II MSC BIOPHYSICS
INTRODUCTION
• Key tool
• Molecular docking is a method which predicts the preferred orientation of one
molecule(Protein) to a second(Ligand) when bound to each other to form a
complex

Source - https://www.creative-proteomics.com/services/molecular-docking-service.htm
MOLECULAR DOCKING MODELS

Year Model Author

1890 Lock and Key Emil Fischer

1958 Induced fit Daniel Koshland


DOCKING METHODOLOGIES
Rigid docking ( Lock and Key):
• The ligand and receptor are both treated as rigid ; ligand fits into the receptor
like lock and key .
• DOCK, FLOG and FTDOCK
Flexible docking (Induced-fit):
• Induced-fit theory takes the lock-and-key theory a step further, stating that the
active site of the protein is continually reshaped by interactions with the ligand.
• Almost all the docking programs have adopted this methodology, such as
AutoDock , FlexX , Glide, GOLD, IFREDA, QXP and Affinity.
DOCKING CAN BE BETWEEN…
• Protein - Ligand
• Protein – Protein
• Protein – Nucleotide
MOLECULAR DOCKING WORKFLOW

This flowchart shows the key steps common to all docking protocols
SELECTION AND PREPARATION
Receptor selection and preparation
• Building the Receptor
• The 3D structure of the receptor should be considered which can be downloaded from
PDB.
• The receptor should be biologically active and stable.
• Identification of the Active Site
• The active site within the receptor should be identified.
• The receptor may have many active sites but the one of the interest should be selected.
• In the absence of knowledge about the binding sites, cavity detection online servers, e.g.
GRID, POCKET, SurfNet, PASS and MMC can be utilized to identify putative active
sites within proteins.
Ligand selection and preparation
• Ligands can be obtained from various databases like ZINC, PubChem or can be sketched using
tools like Chemsketch.
DOCKING
• The ligand is docked onto the receptor
• Docking can be achieved through two interrelated steps:
• First by sampling conformations of the ligand in the active site of the protein
• Then ranking these conformations via a scoring function.
• Sampling conformations of the ligand is done by varies search algorithms used in programs are
• Matching algorithm - DOCK , FLOG , LibDock and SANDOCK
• The incremental construction (IC) method - DOCK 4.0, FlexX , Hammerhead, SLIDE and eHiTS
• Monte Carlo method - AutoDock, ICM, QXP and Affinity
• Genetic algorithm - AutoDock , GOLD , DIVALI and DARWIN
• Fragment-based method - Multiple Copy Simultaneous Search (MCSS) and LUDI
• Molecular dynamics (MD)
SCORING FUNCTION
• The purpose of the scoring function is to delineate the correct poses from
incorrect poses, or binders from inactive compounds.
• Scoring functions involve calculating the binding affinity between the protein
and ligand and through these functions, adopting various assumptions and
simplifications.
• Scoring functions can be divided in:
• Force-field-based scoring functions (DOCK, GOLD and AutoDock)
• Empirical scoring functions (LUDI ,PLP, ChemScore and Glide SP/XP)
• Knowledge-based scoring functions (PMF, DrugScore, SMoG and Bleep)
APPLICATIONS
Drug Discovery
• Docking can be used to predict in where and in which relative orientation a ligand binds to a
protein. This information may in turn be used to design more potent and selective analogs.
• To check the specificity of the potential drug against homologous protein through docking.
Hit identification
• Molecular docking combined with a scoring function can be applied to quickly screen large
databases of potential in silico to identify molecules that are possible to bind to protein target of
interest ..
Lead optimization
• Molecular docking can be applied to predict the binding mode of a ligand binding to a protein.
This information may in turn be applied to design more potent and selective analogs.
Bioremediation
• Protein ligand docking can also be used to predict pollutants that can be degraded by enzymes.
• Study the geometry of a particular complex
DOCKING SOFTWARE

Source - http://www.biocode.it/docking.php
REFERENCE

• Morris G.M., Lim-Wilby M. (2008) Molecular Docking. In: Kukol A. (eds)


Molecular Modeling of Proteins. Methods Molecular Biology™, vol 443.
Humana Press
• Meng, Mihaly Mezei, Xuan-Yu et al. “Molecular docking: a powerful
approach for structure-based drug discovery” Current computer-aided drug
design vol. 7,2 (2011): 146-57.
• YouTube [Internet] : Molecular Docking : Protein-ligand ; Available from:
https://www.youtube.com/watch?v=quXFgP_p5bE&t=1286s