Small Molecule Medicinal Chemistry: Strategies and Technologies by Czechtizky Werngard;Hamley Peter; & Peter Hamley

Author:Czechtizky, Werngard;Hamley, Peter; & Peter Hamley [Czechtizky, Werngard & Hamley, Peter]
Language: eng
Format: epub
Publisher: John Wiley & Sons, Incorporated
Published: 2015-11-02T00:00:00+00:00

Virtual screening is meanwhile a well-accepted method, which is frequently applied in hit and lead identification. This established position is reflected by numerous reviews describing different facets of virtual screening [3–16]. In this chapter, we will focus on requirements and aspects of virtual screening, which we consider as being important for a successful application.

9.1.1 Goals of Virtual Screening

The aim of virtual screening is to identify molecules active against a certain protein. A wealth of different techniques and software programs is available for virtual screening. For example, substructure searching uses a defined chemical substructure to identify other molecules with the same chemical fragments. Various similarity searching methods recognize chemically related molecules as hits of virtual screening searches. Thus, generally close analogues of the query structures are found. Accordingly, these methods are used for the identification of additional analogues of a known biologically active molecule in order to complete the SAR picture from available chemical compounds. On the other extreme, it might be necessary to identify novel chemical structures due to threats of the intellectual property position or due to toxicity issues of the actual chemical series. 3D approaches like molecular docking, which do not rely on a chemical structure of a query molecule, can be used to accomplish such a goal. Success criteria are completely different in these situations. In the first example, many active compounds are beneficial to complete the SAR picture, while in the second case, the hit rate is of less importance, but the number of novel chemical scaffolds identified is much more relevant.

In addition, the available knowledge about the target and its ligands can differ significantly starting from only one active ligand to many different molecules together with a detailed understanding of protein–ligand interactions due to available cocrystal structures. Depending on the actual knowledge and goal of the virtual screening, methods and databases have to be carefully chosen.

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