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Exploring protein hotspots by optimized fragment pharmacophores

Medicine and Health

Exploring protein hotspots by optimized fragment pharmacophores

D. Bajusz, W. S. Wade, et al.

Discover how a team led by Dávid Bajusz and colleagues has harnessed fragment-based drug design to create a pilot library, SpotXplorer0, that successfully identifies hits for challenging targets like SETD2 and SARS-CoV-2. This innovative approach integrates pharmacophores with protein hotspot theory, paving the way for future drug development.

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Playback language: English
Abstract
Fragment-based drug design (FBDD) offers a bottom-up approach to drug development. This study combines pharmacophores (representing drug-target interactions) with protein hotspot theory to develop a fragment library design protocol. The SpotXplorer approach creates small fragment libraries maximizing coverage of experimentally confirmed binding pharmacophores at preferred hotspots. A pilot library (SpotXplorer0) of 96 compounds was validated on various targets, including challenging ones like SETD2, SARS-CoV-2 3CLPro, and NSP3 macrodomain, showing success in identifying hits.
Publisher
Nature Communications
Published On
May 27, 2021
Authors
Dávid Bajusz, Warren S. Wade, Grzegorz Satała, Andrzej J. Bojarski, Janez Ilaš, Jessica Ebner, Florian Grebien, Henrietta Papp, Ferenc Jakab, Alice Douangamath, Daren Fearon, Frank von Delft, Marion Schuller, Ivan Ahel, Amanda Wakefield, Sándor Vajda, János Gerencsér, Péter Pallai, György M. Keserű
Tags
fragment-based drug design
pharmacophores
drug-target interactions
protein hotspot theory
SpotXplorer0
SARS-CoV-2
SETD2

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