Computer-aided Drug Design Group are interested in design of
*Anticoagulant drugs for the treatment of thromboembolic diseases
*Anti-AIDS drugs
*A drug for smoking cessation
AND
*Modelling of Cytochrome P450 enzymes which has a crucial role in the metabolism of drugs.
* Generating a database of thrombin inhibitors
* Assesment of Docking Program FlexX for Thrombin Inhibitors
STRUCTURE-BASED DRUG DESIGN
Drug discovery is very long and expensive process. It takes 12-15 years for a newly identified molecule to go from being discovered, to be tested of its effectiveness and safety on animals and human, to become FDA approved and marketed for public usage. It costs more than 800 million dollars.
Structure-based drug design is used to speed up the drug discovery process. It is a new tool in medicinal chemistry.
APPROACHES USED FOR DRUG DESIGN
HOMOLOGY MODELLING
The knowledge of the three-dimensional structure of a protein is used to derive new protein ligands with improved binding properties. However, it is very difficult task and usually not possible to obtain the three-dimensional structures of these proteins from X-ray diffraction or NMR.
Homology modeling is used to model complete three-dimensional structures of target proteins(thrombin, HIV targets and P450s).
DOCKING
When the structure of the target known, usually from x-ray crystallography or predicted by homology modeling, the most common virtual screening approach is molecular docking. Computational virtual screening will be performed on libraries of known or constructed compounds and requires either measured activities for some known compounds or a structure of the biological target. Libraries of potential ligands are built in computer and scored for potential activity. The top-scoring compounds can then be purchased or synthesized and submitted for experimental testing.
MOLECULAR DYNAMICS SIMULATIONS
Computer simulation methods are becoming an essential tool in many areas of physics, chemistry, and biochemistry.
Molecular dynamics (MD) is a form of computer simulation wherein atoms and molecules are allowed to interact for a period of time under known laws of physics, giving a view of the motion of the atoms. Molecules like proteins and DNA are machines in motion.
The main experimental method for probing and determining protein structure, X-ray diffraction, provides comparatively little information on how the protein moves because crystal structures are inhibitor-bound and may not represent true active-sites and also crystal structures may not represent " true-solvated"systems.
Molecular dynamics computer simulations, on the other hand, are able to yield detailed information on protein dynamics that is very useful, particularly for rational drug design.