Inverse Docking, A novel approach to determine the side effects and toxicity of new drugs

1. A novel Approach to determine side effects &
toxicity of new drugs
VENU THATIKONDA
PI - 15
INVERSE DOCKING

2. Contents…
- Docking
- Introduction to Inverse Docking
- Cavity Database
- Inverse Docking procedure
- Scoring
- References

3. What is Docking?

4. Protein Chemical Database
Hit (Putative ligand)

5. What is the need of Inverse Docking?
to determine Side effects & Toxicity

6. Active compound 3D structures of proteins
Putative target

7. ‘ID’ method includes..
 Protein cavity database
Remove ligand & water
Surface of protein is generated
Generate van der waals surface of a solvent-accessible surface
Fill the protein surface with spheres
Check each sphere for the extent of it’s surrounding
space covered by protein atoms

8. Based on spatial separation of nearest neighboring spheres
devide cavities into different groups
Computer based programs
 CASTp
 fpocket

9.  Inverse Docking procedure
 ‘INVDOCK’ is a program used for Inverse Docking
 Automated search of cavity db.
 All parts of each cavity subjected to docking.
 Docking starts from known ligand binding sites
 To save CPU time, program proceeds to next entry when
successful dock is obtained.
 All cavity entries are subjected to searching.

10.  Scoring
 Based on ligand-protein interaction energy function (ΔELP).
 Computed ΔELP should be less than ΔEThreshold.
ΔEThreshold = -αN kcal/mol.
N – no. of ligand atoms
α – constant
 ‘α’ is determined by fitting linear eq. ΔEThreshold to the
computed ΔELP.
 This statistically derived energy value can be used
empirically as threshold.

11.  ΔELP not only evaluated against ΔEThreshold but also
compared to the ligand-protein interation energy of
corresponding PDB ligands.
Example: 4H- Tamoxifen
 Anti caner drug (Breast cancer).
 Acts through Estrogen receptor.

12. Other potential targets include..
 Alcohol dehydrogenase
 Glutathione transferase
 Collagenase
 Arginase
 Aldose reductase

13.  Reference:
1. Chen YZ, Zhi DG. Ligand-protein inverse docking and its potential
use in the computer search of protein targets of a small molecule.
Proteins. 2001;43:217–226.
2. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D,
Warren JT, Bokesch H, Kenney S, Boyd MR. New colorimetric
cytotoxicity assay for anticancer-drug screening.
J. Natl. Cancer Inst.2012;82:1107–1112.
3. Meng EC, Shoichet BK, Kuntz ID. Automated docking with
grid-based energy approach to macromolecule-ligand interactions.
J. Comput. Chem. 2013;13:505–524.

14. ANY QUESTIONS ??