Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries

TY - JOUR

T1 - Escape from planarity in fragment-based drug discovery

T2 - A physicochemical and 3D property analysis of synthetic 3D fragment libraries

AU - Hamilton, David J.

AU - Dekker, Tom

AU - Klein, Hanna F.

AU - Janssen, Guido V.

AU - Wijtmans, Maikel

AU - O'Brien, Peter

AU - de Esch, Iwan J.P.

N1 - Funding Information: We acknowledge funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie-Skoldowska-Curie grant agreement number 675899 (“Fragment based drug discovery Network, FRAGNET”), the Dutch Research Council under Applied and Engineering Sciences grant number 18019(“Ready for growth: a new generation of highly versatile fragment libraries”) and The Royal Society (Industry Fellowship, INFR1191028). Funding Information: We acknowledge funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie-Skoldowska-Curie grant agreement number 675899 (“Fragment based drug discovery Network, FRAGNET”), the Dutch Research Council under Applied and Engineering Sciences grant number   18019 (“Ready for growth: a new generation of highly versatile fragment libraries”) and The Royal Society (Industry Fellowship, INFR1191028 ). Publisher Copyright: © 2021

PY - 2021/12/9

Y1 - 2021/12/9

N2 - Fragment-based drug discovery (FBDD) has grown into a well-established approach in the pursuit of new therapeutics. Key to the success of FBDD is the low molecular complexity of the initial hits and this has resulted in fragment libraries that mainly contain compounds with a two-dimensional (2D) shape. In an effort to increase the chemical diversity and explore the impact of increased molecular complexity on the hit rate of fragment library screening, several academic and industrial groups have designed and synthesised novel fragments with a three-dimensional (3D) shape. This review provides an overview of 25 synthetic 3D fragment libraries from the recent literature. We calculate and compare physicochemical properties and descriptors that are typically used to measure molecular three-dimensionality such as fraction sp3 (Fsp3), plane of best fit (PBF) scores and principal moment of inertia (PMI) plots. Although the libraries vary widely in structure and properties, some key common features can be identified which may have utility in designing the next generation of 3D fragment libraries.

AB - Fragment-based drug discovery (FBDD) has grown into a well-established approach in the pursuit of new therapeutics. Key to the success of FBDD is the low molecular complexity of the initial hits and this has resulted in fragment libraries that mainly contain compounds with a two-dimensional (2D) shape. In an effort to increase the chemical diversity and explore the impact of increased molecular complexity on the hit rate of fragment library screening, several academic and industrial groups have designed and synthesised novel fragments with a three-dimensional (3D) shape. This review provides an overview of 25 synthetic 3D fragment libraries from the recent literature. We calculate and compare physicochemical properties and descriptors that are typically used to measure molecular three-dimensionality such as fraction sp3 (Fsp3), plane of best fit (PBF) scores and principal moment of inertia (PMI) plots. Although the libraries vary widely in structure and properties, some key common features can be identified which may have utility in designing the next generation of 3D fragment libraries.

UR - http://www.scopus.com/inward/record.url?scp=85108543638&partnerID=8YFLogxK

U2 - 10.1016/j.ddtec.2021.05.001

DO - 10.1016/j.ddtec.2021.05.001

M3 - Review article

C2 - 34895643

AN - SCOPUS:85108543638

SN - 1740-6749

VL - 38

SP - 77

EP - 90

JO - Drug Discovery Today: Technologies

JF - Drug Discovery Today: Technologies

ER -