Virtual Screening in Drug Discovery

The goal of screening small molecules for drug discovery is to deliver new hit compounds to medicinal chemists that can act as starting points for the development of drug candidates. Computational chemistry and molecular modeling provide tools that are commonly used to direct and increase the efficiency of laboratory screening by selecting or designing compounds to be tested (Bajorath, 2002; Jorgensen, 2004; Walters and Namchuk, 2003). This is driven by the fact that the number of compounds available for screening usually far exceeds the number that will actually go into the screen. Similar methods are then applied in the hit or lead optimization process; however, this review will mainly focus on the methodologies that are applied to computer-based, in silico, or ‘‘virtual’’ screening in the early stages of drug discovery. Theprecisedefinitionofa‘‘hit’’or‘‘lead’’moleculevaries fromoneorganization to another. At Serono, a compound from screening is regarded as a hit if it has favorable properties in thefollowingrespects: (i)potencyinabiologicalorbiochemicalassay, (ii) novelty with regard to intellectual property, (iii) selectivity for the intended target, and (iv) tractability in terms of ease of synthesis. A lead has the properties of a hit plus a