Dear Raja,

Protein based drug design and structure based drug design are the same approach.However, there are structure-based and ligand-based drug design where the first refers to the protein (the target) and the second to the ligand (agonist, antagonist or inhibitor). In protein based drug design the 3D of the active site of the protein (enzyme or receptor) is known where in the second the chemical structure of the ligand that binds to the active site is known.

The following text illustrates the steps considered in structure based drug design:

Structure-Based Drug Design

The process of structure-based drug design is an iterative one and often proceeds through multiple cycles before an optimized lead goes into phase I clinical trials. The first cycle includes the cloning, purification and structure determination of the target protein or nucleic acid by one of three principal methods: X-ray crystallography, NMR, or homology modeling. Using computer algorithms, compounds or fragments of compounds from a database are positioned into a selected region of the structure. These compounds are scored and ranked based on their steric and electrostatic interactions with the target site, and the best compounds are tested with biochemical assays. In the second cycle, structure determination of the target in complex with a promising lead from the first cycle, one with at least micromolar inhibition in vitro, reveals sites on the compound that can be optimized to increase potency. Additional cycles include synthesis of the optimized lead, structure determination of the new target:lead complex, and further optimization of the lead compound. After several cycles of the drug design process, the optimized compounds usually show marked improvement in binding and, often, specificity for the target.

For more information, please see the review article contained in the following link:

http://www.sciencedirect.com/science/article/pii/S1074552103001947

Hoping this will be helpful,

Rafik