Computer-aided drug design has become an essential aspect of drug discovery, significantly accelerating the processes of discovery and lead optimization. Here, we focus on anchor-centered docking approaches. A few years ago, we introduced the pharmacophore-based virtual screening platform ANCHOR.QUERY (http://anchorquery.ccbb.pitt.edu/), which includes novel compounds that can be easily synthesized using multi-component reactions and commercially available starting materials. ANCHOR.QUERY was successfully applied to the protein–protein interaction of p53–MDM2 and the discovery of allosteric inhibitors of the PDK1 kinase. However, ANCHOR.QUERY was made for the design of small molecule PPI antagonists and therefore, it is based on the often overarching energy contribution of deeply buried large amino acid side chains in the receptor pockets, often called “hot spots”. Often an energetically hot spot consists of a synthetic fragment in which case the amino acid side chain centered ANCHOR.QUERY database cannot be employed.<br/><br/>Here, we describe the development of a docking protocol for tailor-made virtual libraries with flexible fragments as anchor points. In a case study on aspartic proteases we designed a novel warhead which is incorporated in an easily accessible multi-component reaction scaffold. Initial screening and protein crystallography-supported hits could be rapidly improved towards more potent binders in a small number of optimization rounds. The pipeline of anchor-centred docking, innovative chemistry and screening will be applicable in many different targets for the discovery of novel leads.

Inhibitors for Asp-proteases: Anchor-based virtual screening, innovative chemistry, and protein crystallography

2019 Spring National Meeting

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