A novel Approach to determine side effects & toxicity of new drugs

VENU THATIKONDA PI - 15

INVERSE DOCKING

Contents…

- Docking- Introduction to Inverse Docking- Cavity Database- Inverse Docking procedure- Scoring- References

What is Docking?

Protein Chemical Database

Hit (Putative ligand)

What is the need of Inverse Docking?

to determine Side effects & Toxicity

Active compound 3D structures of proteins

Putative target

‘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

Based on spatial separation of nearest neighboring spheres devide cavities into different groups

Computer based programs

CASTp fpocket

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.

Scoring Based on ligand-protein interaction energy function (ΔELP). Computed ΔELP should be less than ΔEThreshold.

ΔEThreshold = -αN kcal/mol.N – no. of ligand atomsα – constant

‘α’ is determined by fitting linear eq. ΔEThreshold to the computed ΔELP.

This statistically derived energy value can be used empirically as threshold.

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.

Other potential targets include..

Alcohol dehydrogenase Glutathione transferase Collagenase Arginase Aldose reductase

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.

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