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Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.

ABSTRACT: Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high-affinity, drug-like ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from a protein 3D structure, and how their strength, number, and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery.

SUBMITTER: Hall DR

PROVIDER: S-EPMC4640985 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.

Hall David R DR Kozakov Dima D Whitty Adrian A Vajda Sandor S

Trends in pharmacological sciences 20151101 11

Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high-affinity, drug-like ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from a protei ...[more]

PMID: 26538314

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