This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design

1. PRESENTED BY
GAUTAM J KHUNE
M . Pharmacy 1stYear
(Department of
Pharmacology)
GUIDED BY:-
Dr. Shvetank Bhatt
Associate Professor
Dept. of Pharmacology
R.C.Patel Institute Of Pharmaceutical Education And Research, Shirpur

2. CONTENT
INTRODUCTION TO MOLECULAR DOCKING
 DEFINITION
 RIGID DOCKING
 FLEXIBLE DOCKING
 MANUAL DOCKING
 DOCKING BASED SCREENING
 DE-NOVO DRUG DESIGN

3. DRUG DISCOVERY
• Drug discovery take years to decade for discovering a new drug.
• Effort to cut down the research timeline and cost by reducing wet-lab experiment
use computer modelling.
• Drugs interact with their receptors in a highly specific and complementary
manner.

4. WHAT IS DOCKING?
Docking is a structure-based technique which attempts to find the “best”
match, between two molecules.

5. •DEFINITION…
• Molecular docking can be defined as the binding of small molecule called
ligand , on to a specific site in a larger molecule
• Docking is the computational determination of binding affinity between
molecules (protein structure and ligand).

6. IMPORTANCE OF DOCKING
• It is the key to rational drug design.
• The results of docking can be used to find inhibitors for specific target proteins
and thus to design new drugs.
• It is gaining importance as the number of proteins whose structure is known
increases.
• Identification of the ligand’s Correct binding geometry (pose) in the binding site.
• Signal transduction

7. DOCKING GLOSSARY
 Receptor or host or lock: the "receiving" molecule, most commonly a protein or other biopolymer.
 Ligand or guest or key: the complementary partner molecule which binds to the receptor. Ligands are most often small
molecules but could also be another biopolymer.
 Docking: computational simulation of a candidate ligand binding to a receptor.
 Binding mode: the orientation of the ligand relative to the receptor as well as the conformation of the ligand and receptor when
bound to each other.

8. CONTINUE..
Pose : a candidate binding mode.
Scoring : the process of evaluating a particular pose by counting the number of favorable intermolecular
interactions such as hydrogen bonds and hydrophobic contacts.
Ranking : the process of classifying which ligands are most likely to interact favorably to a particular
receptor based on the predicted free-energy of binding

9. TYPES OF DOCKING
1.Rigid docking
2.Flexible docking
3.Manual docking

10. RIGID DOCKING
In the rigid docking molecules are rigid, in 3D space of one of the molecule which brings it to an optimal fit with the other
molecules in terms of a scoring function.
Historically the first approaches.
• Protein and ligand are fixed.
• Search for the relative orientation of the two molecules with lowest energy.
• Protein-Protein Docking
• Both molecules usually considered rigid

11. (LOCK AND KEY)
• Finding the correct relative orientation of the “key” which will open up the “lock”.
• On the surface of the lock is the key hole…
• 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 coloured P51 subunit &
red coloured
P66 subunit

12. FLEXIBLE DOCKING
• In flexible docking molecules are flexible ,confirmations of the receptor and the Ligand molecules , as they appear in
complex.
• Protein-ligand docking
• Flexible ligand, rigid receptor
• Search space much larger
• Either reduce flexible ligand
• An enumeration on the rotations of one of the molecules (usually smaller one) is performed. Every rotation the energy is
calculated; later the most optimum pose is selected.

13. Ligand is flexible but the receptor protein is rigid. Interaction
produces conformational changes in ligand

14. MANUAL DOCKING
• Looks like a joke... The ligand is placed in the interacting site and the association energy is calculated at
each steps.
• The user manually moves, rotates or translates the compound inside the protein cavity. A new association
energy is recorded... Etc
• Advantages: quick , Can be very efficient if the user knows well the interacting site
• Drawbacks: users dependant ,you can really obtain stupid results this rudimentary method surprisingly
provided interesting results in the past.
• It is still applicable if only small ligand modifications are explored.

15. DOCKING BASED SCREENING
The docking based screening was performed in 3 screening protocol, starting with HTVS followed by SP and XP methods.
The high throughput virtual screening (htvs) mode is designed to screen large libraries quickly with rough scoring functions,
hence to screen 8.5 million compounds we started with this method.
 The top ranked hits (top 20%) were passed through standard precision (SP) mode, which is ten times slower and more precise
than HTVS. The sp method is more exhaustive in conformational sampling and more precise than htvs method with the expense
of time.
About 20,000 compounds obtained from sp method (best 50% of the compounds) were further evaluated with even more
precise and more computationally intensive extra precision (xp) method.

16. About 1000 compounds obtained from XP method were shortlisted based on docking score that are -9.0
and above.
 The high glide score indicated a high binding affinity towards the target.
We checked for the following interactions, hydrogen bonds, salt bridges, halogen bonds, aromatic bonds,
pi-cation and also pi-pi interactions all of which contribute towards the stability of the protein-ligand
complexes
continue..

17. DE NOVO DRUG DESIGN
• De novo design is the approach to build a customized ligand for a given receptor.
• This approach involves the ligand optimization.
• Ligand optimization can be done by analyzing protein active site properties that could be probable area of
contact by the ligand.
• The analyzed active site properties are described to negative image of protein such as hydrogen bond,
hydrogen bond acceptor and hydrophobic contact region.

18. CONTINUE
• De novo means start afresh, from the beginning, from the scratch
• It is a process in which the 3d structure of receptor is used to design newer molecules
• It involves structural determination of the lead target complexes and lead modifications using molecular
modeling tools.
• Information available about target receptor but no existing leads that can interact.

19. •Assembling possible compounds and evaluating their quality.
• Searching the sample space for novel structures with Drug like properties.
PRINCIPLES OF DENOVO DRUG DESIGN
Protein Structure Build a model for Protein Structure

20. CONTINUE..
• In de novo design, the structure of the target should be known to a high resolution, and the
binding to site must be well defined.
• This should defines not only a shape constraint but hypothetical interaction sites, typically
consisting of hydrogen bonds, electrostatic and other non-covalent interactions.
• These can greatly reducing the sample space, as hydrogen bonds and other anisotropic
interactions can define specific orientations.

21. SOFTWARES USED IN DOCKING
• SANJEEVINI -IIT delhi
(www.Scfbioiitd.Res.In/sanjeevini/sanjeevini.Jsp
• GOLD – university of cambridge ,U(www.Ccdc.Cam.Ac.Uk/solutions/goldsuite/pages/GOLD.Aspx)
• AUTODOCK - scripps research institute,usa (autodock.Scripps.Edu/)
• 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/)
• Hex protein docking - 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/)

22. APPLICATIONS
Structure
based drug
design
Lead
Optimization
Virtual
Screening of
large
databases
Protein-
Protein
Docking
Bio
remediation

23. REFERENCES
• FOYE’S PRINCIPLES OF MEDICINAL CHEMISTRY-SIXTH EDITION, PUBLISHED BY LIPPINCOTT
WILLIAMS AND WILKINS, PAGE NUM-69-70
• PROTEIN-LIGAND DOCKING METHODS; THOMAS FUNKHOUSER;PRINCETON UNIVERSITY
• AN INTRODUCTION TO MEDICINAL CHEMISTRY; 4TH EDITION; GRAHAM.L.PATRICK; PG NO.
352-361
• LENGAUER T, RAREY M (JUN 1996). "COMPUTATIONAL METHODS FOR BIOMOLECULAR
DOCKING". CURRENT OPINION IN STRUCTURAL BIOLOGY. 6 (3): 402–6
• SCHNEIDER G.; FECHNER U.; “COMPUTER-BASED DE NOVO DESIGN OF DRUG-LIKE
MOLECULES.” NAT REV DRUG DISCOVER 2005 AUG; 4(8), 649- 63. REVIEW

24. THANKYOU