A New Approach to Design Matrix metalloprotienase Inhibitors

Venu ThatikondaM.S(pharm)- PI-15

Introduction of MMP Role in cancer MMP-inhibitors Computer Aided Drug Design Virtual screening Docking

Contents

MMP’s

Matrix metalloprotienases are Zn-dependent endopeptidases.

Catalytic domain contains 2 ‘Zn’ atoms. Degrades all kinds of extracellular matrix proteins.

MMP’sRole in CANCER :

Increased IGF by cleaving IGF-BP

Cleavage of FAS ligand

Regulate ‘Invasion & Metastasis’

MMP’s Promote Angiogenesis by increasing the levels of

VEGF FGF-2 TGF

MMP-Inhibitors Drugs which inhibit the activities of these MMP’s are helpful in the treatment of cancer

Eg – Batimastat (BB-94)

A new approach to design these drugs is “Computer Based Drug Designing”

Determination of Crystal structure of Target

Drawing 2D structure

Converting it to 3D using computers

The concept of CBDD includes..

Continues..

‘Virtual screening’ of Chemical libraries(Ligands)

‘Docking’ of ligand & Target

Hit compound evaluation

In-vivo experiments

Virtual screening :Automatically evaluating very large libraries of compounds using computer programs.

- Ligand based

- Structure based

Virtual screening

Docking :

It is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex.

Docking

After Docking evaluation is done for the size, chemical, Physilogical properties through 3D QSAR

Hit compound evaluation in-vivo

Refference : Rollinger JM, Stuppner H, Langer T (2008). "Virtual screening for the discovery of bioactive natural products". Prog Drug Res. Progress in Drug Research 65 (211): 213–49.

"Pharmacophore-based virtual screening". Curr Med Chem 15 (10): 1018–24.

"Computational methods for biomolecular docking". Curr. Opin. Struct. Biol. 6 (3): 402–6.

Any Questions ??

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