Drug design

Drug design, also sometimes referred to as rational drug design, is the inventive process of finding new medications based on the knowledge of the biological target. The drug is most commonly an organic small molecule which activates or inhibits the function of abiomolecule such as a protein which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves design of small molecules that are complementary in shape and charge to the biomolecular target to which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is often referred to as computer-aided drug design.

The phrase '"drug design" is to some extent a misnomer. What is really meant by drug design is ligand design. Modeling techniques for prediction of binding affinity are reasonably successful. However there are many other properties such as bioavailability, metabolic half life, lack of side effects, etc. that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.

Types

Flow charts of two strategies of structure-based drug design

There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design.

Ligand based

Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophorewhich defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. In other words, a model of the biological target may be built based on the knowledge of what binds to it and this model in turn may be used to design new molecular entities that interact with the target.

Structure based

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.^[4] If an experimental structure of a target is not available, it may be possible to create a homology model of the target based on the experimental structure of a related protein. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity andselectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.

As experimental methods such as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically. In parallel, information about the structural dynamics and electronic properties about ligands has also increased. This has encouraged the rapid development of the structure-based drug design. Current methods for structure-based drug design can be divided roughly into two categories. The first category is about “finding” ligands for a given receptor, which is usually referred as database searching. In this case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This method is usually referred as ligand-based drug design. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. Another category of structure-based drug design methods is about “building” ligands, which is usually referred as receptor-based drug design. In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested. These techniques are raising much excitement to the drug design community.