Drug discovery is the process by which new candidate medications are discovered. Historically, drug discovery was based on natural products extracted from plants and animals. More recently, chemical libraries of synthetic small molecules are used. Usually, the development process begins with the discovery of a lead compound that exhibits the desired biological activity likely to be useful. Afterwards, organic chemists perform studies of structure-activity relationship (SAR) to synthesize derivatives of the lead compound with optimized pharmacokinetic or pharmacodynamic properties. These derivatives are called analogues.
The process of drug discovery and development is a very demanding process that requires the collaborative effort of scientists, governments, and pharmaceutical corporations. The cost of discovering, optimizing, testing and putting a new drug in the market is estimated to be 1.8 billion USD. To be allowed to come to market, drugs must undergo several successful phases of clinical trials, and pass through a new drug approval process, called the New Drug Application in the United States.
Schematic diagram of drug discovery cycle. Image by Boghog, CC BY-SA 4.0, via Wikimedia Commons
Lead compound is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target. Lead drugs offer the prospect of being followed by back-up compounds called analogs. Its chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly invented pharmacologically active moieties may have poor drug-likeness and may require chemical modification to become drug-like enough to be tested biologically or clinically.
A structural analog, also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analog can be imagined to be formed, at least theoretically, from the other compound.
Despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very different physical, chemical, biochemical, or pharmacological properties. In drug discovery either a large series of structural analogs of an initial lead compound are created and tested as part of a structure–activity relationship study or a database is screened for structural analogs of a lead compound.
Figure 1. Example of a lead compound (salicylic acid) and its analog (acetylsalicylic acid)
A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response". A pharmacophore region of a drug is responsible for its biological action, and this model explains how structurally diverse ligands can bind to a common receptor site.
Figure 2. Examples of pyrimidine derivatives used as potential drugs in the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction. and urinary incontinence. The pharmacophore region of each molecule is indicated in red.
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