Structure-Based Drug Design (SBDD) : Positive Approach For Drug Discovery

Structure-based drug design is one of several methods in the rational drug design toolbox. Drug targets are typically key molecules involved in a specific metabolic or cell signaling pathway that is known, or believed, to be related to a particular disease state. Drug targets are most often proteins and enzymes in these pathways. Drug compounds are designed to inhibit, restore or otherwise modify the structure and behaviour of disease-related proteins and enzymes. SBDD uses the known 3D geometrical shape or structure of proteins to assist in the development of new drug compounds. The 3D structure of protein targets is most often derived from x-ray crystallography or nuclear magnetic resonance (NMR) techniques. X-ray and NMR methods can resolve the structure of proteins to a resolution of a few angstroms (about 500,000 times smaller than the diameter of a human hair). At this level of resolution, researchers can precisely examine the interactions between atoms in protein targets and atoms in potential drug compounds that bind to the proteins. This ability to work at high resolution with both proteins and drug compounds makes SBDD one of the most powerful methods in drug design.The beauty of the SBDD method is the extremely high level of detail that it reveals about how drug compounds and their protein targets interact.

Docking Ligands : One of the key benefits of SBDD methods is the exceptional capability it provides for docking putative drug compounds (ligands) in the active site of target proteins. Most proteins contain pockets, cavities, surface depressions and other geometrical regions where small-molecule compounds can easily bind. With high-resolution x-ray and NMR structures for proteins and ligands, researchers can show precisely how ligands orient themselves in protein active sites. Open source bioinformatics tools such as VMD and NAMD, for example, help scientists examine multiple binding poses to determine which orientation is most likely to occur.

Furthermore, it’s well known that proteins are often flexible molecules that adjust their shape to accommodate bound ligands. In a process called molecular dynamics, SBDD allows researchers to dock ligands into protein active sites and then visualize how much movement occurs in amino acid side chains during the docking process. In some cases, there is almost no movement at all (i.e., rigid-body docking); in other cases, such as with the HIV-1 protease enzyme, there is substantial movement. Flexible docking can have profound implications for designing small-molecule ligands so this is an important feature in SBDD methods.

Lead Optimization : After a number of lead compounds have been found, SBDD techniques are especially effective in refining their 3D structures to improve binding to protein active sites, a process known as lead optimization. In lead optimization researchers systematically modify the structure of the lead compound, docking each specific configuration of a drug compound in a protein’s active site, and then testing how well each configuration binds to the site. In a common lead optimization method known as bioisosteric replacement, specific functional groups in a ligand are substituted for other groups to improve the binding characteristics of the ligand. With SBDD researchers can examine the various bioisosteres and their docking configurations, choosing only those that bind well in the active site. A few examples of bioinformatics tools that aid in lead optimization efforts are BIOSTER, WABE, and ClassPharmer Suite.

For further information about SBDD please see the following references –

1) Wang R,Gao Y,Lai L (2000). “LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design”. Journal of  Molecular Modeling 6 (7–8): 498–516.

2 ) Verlinde CL, Hol WG (July 1994). “Structure-based drug design: progress, results and challenges”. Structure 2 (7): 577–87.

3) Tollenaere JP (April 1996). “The role of structure-based ligand design and molecular modelling in drug discovery”. Pharm World Sci 18 (2): 56–62.