Construction of a Shape‐Diverse Fragment Set: Design, Synthesis and Screen against Aurora‐A Kinase

Abstract

Historically,c hemists have explored chemical space in ah ighly unevena nd unsystematic manner.A sa n example, the shape diversity of existing fragments ets does not generally reflect that of all theoretically possible fragments. To assess experimentallyt he added value of increased three dimensionality,ashape-diverse fragment set was designed and collated. The set was assembled by both using commerciallya vailable fragments and harnessing unified synthetic approaches to sp 3 -rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimen-sional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators.I nt he longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.[a] Dr.(South Africa)[g] Prof. R. Bayliss SchoolofM olecular and Cellular Biology,U niversity of Leeds Leeds, LS2 9JT (UK)Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…[24] Desirable properties have also made the elementp articularly useful for NMR spectroscopy. 19 Fi s1 00 %n aturallya bundant and exhibits aw ide chemical-shiftr ange, spanning severalh undred ppm, which enables the routine screening of cocktails containing ! 30 fragments.…”

“…[23,25] 19 FNMR spectroscopy screening typically relies on transverse (T 2 )r elaxation-based experiments.T hese exploit the large differencei nt umbling rates between large biomolecules and fragments, along with ac hemical exchange contribution that arises from the difference in chemical shifts between free and bound states ( Figure 1). The following sectionh ighlights a few examples of fluorinated fragment libraries used for 19 FNMR spectroscopy screening. For am ore detailed analysis of the principles and application of 19 FNMR spectroscopy screening in drug discovery,r eaders are referred to an extensive review recently published.…”

“…The following sectionh ighlights a few examples of fluorinated fragment libraries used for 19 FNMR spectroscopy screening. For am ore detailed analysis of the principles and application of 19 FNMR spectroscopy screening in drug discovery,r eaders are referred to an extensive review recently published. [25] Since the first reports on the use of 19 FNMR spectroscopy for compound screening, [26,27] the technique has increased in popularity in both industry and academia.…”

“…For am ore detailed analysis of the principles and application of 19 FNMR spectroscopy screening in drug discovery,r eaders are referred to an extensive review recently published. [25] Since the first reports on the use of 19 FNMR spectroscopy for compound screening, [26,27] the technique has increased in popularity in both industry and academia. In 2012, Amgen sharedt heir experiences with the practical applications of 19 FNMR spectroscopy screening:alibraryo f1 200 fluorinated fragments was constructed from both commercial and inhouse sourcesbyusing variouscriteria, including adiversity selectionf ilter,toa chieve an approximate 30 %c overage of available fragment space.…”

“…[11,12] Other important considerations include the removal of undesired functional groups(reactive, toxic, or those pronet og enerating false positives), [13][14][15] as well as achieving good libraryd iversity,t oe nsure better sampling of chemical space.A lthough diversityi sarather subjective term, it is often associated with the inclusion of different pharmacophores and, more recently,e specially focusedo ni ncreasings hape diversity and "three-dimensionality." [16][17][18][19][20] However,a lthough diversity is generally important fort argeting different classes of targets, focusedl ibraries against specific targets have their inherent advantages. [10] Despite the advances of FBDD, [2,5] the approach is still limited by laboriouss creening workflows and with hit-to-candidate progression that is not necessarily faster than that of HTS.…”