Traditional methods of drug discovery rely on in vitro and in vivo trial-and-error testing of chemical substances on cultured cells or animals, and extrapolating the observed effects to potential treatment regimens. Compounds are initially screened to narrow in on the ones that have some degree of activity. If these compounds share common chemical features, one or more pharmacophores are then developed. At this point, medicinal chemists attempt to use structure-activity relationships to improve certain features (activity against the chosen target, reduce activity against unrelated subjects) of the lead compound to make it more effective and safe.
Another important method for drug discovery is rational drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might fit into an active site. Novel pharmacophores can emerge very rapidly from these exercises. The biomarker strategy is recommended to be an integral part of drug design that a company undertakes. This allows for stratification of patients and account for genetic variations. These biomarkers ultimately guide the treatment choices and improve the quality of care that patients receive.
There are four different methodologies commonly used in the drug design.
Ligand-Based Drug Design (or indirect drug design): It relies on knowledge of other molecules that bind to the biological target of interest, which may be used to derive a pharmacophore model that will define the minimum necessary structural characteristics a molecule must possess in order to bind to the target.
Structure-Based Drug Design (or direct drug design): This relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. Using the structure of the biological target, candidate drugs are predicted that will bind with high affinity and selectivity to the target. Interactive graphics and the intuition of a medicinal chemist are further used in this design process.
Rational Drug Design: It begins with a hypothesis that modulation of a specific biological target may have therapeutic value compared to traditional design that relies in trial-and-error.
Computer-Assisted Drug Design: This methodology uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal of this methodology is to predict the binding affinity of a given molecule to a target and the associated binding kinetics.