X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design

ACS Omega
Erik GilbergJürgen Bajorath

Abstract

Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand-target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the an...Continue Reading

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Citations

May 31, 2020·International Journal of Molecular Sciences·Christian Feldmann, Jürgen Bajorath
Nov 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Christian FeldmannJürgen Bajorath
Feb 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Christian Feldmann, Jürgen Bajorath
Dec 4, 2019·Journal of Computer-aided Molecular Design·Filip Miljković, Jürgen Bajorath
May 29, 2021·RSC Medicinal Chemistry·Dagmar StumpfeJürgen Bajorath
Dec 5, 2019·Journal of Chemical Information and Modeling·Luca Pinzi, Giulio Rastelli
Jan 13, 2018·Journal of Medicinal Chemistry·Erik GilbergJürgen Bajorath

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Methods Mentioned

BETA
X-ray
multiple

Software Mentioned

RStudio
ChEMBL
house Perl
Zenodo
OpenEye
Molecular Operating Environment
Python scripts

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