Abstract:
:Selectivity is a central aspect of lead optimization in the drug discovery process. Medicinal chemists often try to decrease molecular flexibility to improve selectivity, given the common belief that the two are interdependent. To investigate the relationship between polypharmacology and conformational flexibility, we mined the Protein Data Bank and constructed a dataset of pharmaceutically relevant ligands that crystallized in more than one protein target while binding to each co-crystallized receptor with similar in vitro affinities. After analyzing the molecular conformations of these 100 ligands, we found that 59 ligands bound to different protein targets without significantly changing conformation, suggesting that there is no distinct correlation between conformational flexibility and polypharmacology within our dataset. Ligands crystallized in similar proteins and highly ligand-efficient compounds with five or fewer rotatable bonds were less likely to adjust conformation when binding.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
He MW,Lee PS,Sweeney ZKdoi
10.1002/cmdc.201402389subject
Has Abstractpub_date
2015-02-01 00:00:00pages
238-44issue
2eissn
1860-7179issn
1860-7187journal_volume
10pub_type
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