DEFINITION AND MEANING OF MOLECULAR DOCKING
- Molecular docking is the study of how two or more molecular structures (e.g., drug and enzyme or protein) fit together
- If we explain more- Docking is a method that predicts the preferred orientation of one ligand when bound in an active site to form a stable complex.
- Docking of a small molecule ligand (brown) with a protein receptor (green) to produce a complex.
- Used For : To achieve an optimized conformation for both receptor and ligand & the relative orientation between protein and ligand such that the free energy of the overall system is minimized
- Successful docking methods search high-dimensional spaces effectively and use a scoring function that correctly ranks candidate dockings.
LOCK AND KEY STRUCTURE IN MOLECULAR DOCKING
- Finding the correct relative orientation of the “key” will open up the “lock”.
- On the surface of the lock is the keyhole.
- In which direction to turn the key after it is inserted.
- The protein can be thought of as the “lock” and the ligand can be thought of as a “key”.
- NVP: Nevirapine Crystallographic structure of HIV-1 reverse transcriptase: green colored P51 subunit & red colored P66 subunit
IMPORTANCE of Molecular Docking
It contributes to the Rational Designing of Drugs.
Molecular Docking Prediction of the binding affinity (Scoring Function) Identification of the ligand’s correct binding geometry (pose) in the binding site (Binding Mode) Rational Design Of Drugs
Docking can be between
- Protein-Ligand
- Protein-Protein
- Protein – Nucleotide
Rigid Docking (Lock and Key) – In rigid docking, the internal geometry of both the receptor and ligand are treated as rigid.
Flexible Docking (Induced fit):- An enumeration of the rotations of one of the molecules (usually smaller ones) is performed. Every rotation the energy is calculated; later the most optimum pose is selected.
TYPES OF INTERACTIONS
Steric forces – These are caused by entropy. For example, in cases where entropy is limited, there may be forces to minimize the free energy of the system.
Solvent-related forces – These are due to the structural changes of the solvent. These structural changes are generated, when ions, colloids, proteins, etc, are added to the structure of the solvent. The most common are Hydrogen bond and hydrophobic interactions
Electrostatic forces – Forces with electrostatic origin are due to the charges residing in the matter.
Electrodynamics forces – The most widely known is probably the van der Waals interaction.
Key stages in docking
- Target/Receptor selection and preparation
- Ligand selection and preparation
- Docking
- Evaluating docking results
A typical docking workflow
- Target Selection
- Ligand Selection
- Target Preparation
- Evaluating Docking
- Result Docking
- Ligand Preparation
Receptor selection and preparation Building the Receptor The 3D structure of the receptor should be considered which can be downloaded from PDB. The available structure should be processed. 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 interest should be selected.
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 and the interactions are checked. The scoring function generates a score, depending on which the best fit ligand is selected.
Software and Tools used in the process
- GemDock(Generic Evolutionary Method for Molecular Docking) – A tool, developed by Jinn-Moon Yang, a professor of the Institute of Bioinformatics, National Chiao Tung University, Taiwan (gemdock.life.nctu.edu.tw/dock/)
- SANJEEVINI – By IIT Delhi (www.scfbio-it.res.in/sanjeevini/sanjeevini.jsp)
- GOLD – By University of Cambridge, UK (www.ccdc.cam.ac.uk/Solutions/GoldSuite/Pages/GOLD.aspx)
- Hex Protein Docking – By the University of Aberdeen, UK (hex.loria.fr/)
- GRAMM (Global Range Molecular Matching) Protein docking – A Center for Bioinformatics, University of Kansas, USA (www.bioinformatics.ku.edu/files/vakser/gramm/)
- AUTODOCK – By Scripps Research Institute, USA (autodock.scripps.edu/)
- Hex Protein Docking – By the University of Aberdeen, UK (hex.loria.fr/)
Applications of Molecular Docking
• Virtual screening (hit identification) docking:- with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest.
• Bioremediation Protein-ligand docking:- can also be used to predict pollutants that can be degraded by enzymes.
• Drug Discovery (lead optimization) docking:- can be used to predict where and in which relative orientation a ligand binds to a protein (binding mode or pose). This information may in turn be used to design more potent and selective analogs
If you want to know more about Molecular Docking & MD Simulation in depth you can join us for a 3 Hours Short Course on Drug Discovery, you can register HERE
A brief introduction to Molecular Docking & MD Simulation can be accessed HERE for better understanding of the process.