PMID- 33351593
OWN - NLM
STAT- MEDLINE
DCOM- 20210923
LR  - 20210923
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 34
IP  - 2
DP  - 2021 Feb 15
TI  - Systematic Analysis of Protein Targets Associated with Adverse Events of Drugs 
      from Clinical Trials and Postmarketing Reports.
PG  - 365-384
LID - 10.1021/acs.chemrestox.0c00294 [doi]
AB  - Adverse drug reactions (ADRs) are undesired effects of medicines that can harm 
      patients and are a significant source of attrition in drug development. ADRs are 
      anticipated by routinely screening drugs against secondary pharmacology protein 
      panels. However, there is still a lack of quantitative information on the links 
      between these off-target proteins and the reporting of ADRs in humans. Here, we 
      present a systematic analysis of associations between measured and predicted in 
      vitro bioactivities of drugs and adverse events (AEs) in humans from two sources 
      of data: the Side Effect Resource, derived from clinical trials, and the Food and 
      Drug Administration Adverse Event Reporting System, derived from postmarketing 
      surveillance. The ratio of a drug's therapeutic unbound plasma concentration over 
      the drug's in vitro potency against a given protein was used to select proteins 
      most likely to be relevant to in vivo effects. In examining individual target 
      bioactivities as predictors of AEs, we found a trade-off between the positive 
      predictive value and the fraction of drugs with AEs that can be detected. 
      However, considering sets of multiple targets for the same AE can help identify a 
      greater fraction of AE-associated drugs. Of the 45 targets with statistically 
      significant associations to AEs, 30 are included on existing safety target 
      panels. The remaining 15 targets include 9 carbonic anhydrases, of which CA5B is 
      significantly associated with cholestatic jaundice. We include the full 
      quantitative data on associations between measured and predicted in vitro 
      bioactivities and AEs in humans in this work, which can be used to make a more 
      informed selection of safety profiling targets.
FAU - Smit, Ines A
AU  - Smit IA
AUID- ORCID: 0000-0002-1772-6487
AD  - Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 
      1EW, United Kingdom.
FAU - Afzal, Avid M
AU  - Afzal AM
AD  - Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 
      1EW, United Kingdom.
FAU - Allen, Chad H G
AU  - Allen CHG
AD  - Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 
      1EW, United Kingdom.
FAU - Svensson, Fredrik
AU  - Svensson F
AUID- ORCID: 0000-0002-5556-8133
AD  - Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 
      1EW, United Kingdom.
FAU - Hanser, Thierry
AU  - Hanser T
AD  - Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United 
      Kingdom.
FAU - Bender, Andreas
AU  - Bender A
AUID- ORCID: 0000-0002-6683-7546
AD  - Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 
      1EW, United Kingdom.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201222
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Pharmaceutical Preparations)
RN  - 0 (Proteins)
SB  - IM
MH  - Clinical Trials as Topic
MH  - Humans
MH  - Molecular Structure
MH  - Pharmaceutical Preparations/blood/*chemistry
MH  - Proteins/*analysis/antagonists & inhibitors
MH  - United States
MH  - United States Food and Drug Administration
EDAT- 2020/12/23 06:00
MHDA- 2021/09/24 06:00
CRDT- 2020/12/22 17:10
PHST- 2020/12/23 06:00 [pubmed]
PHST- 2021/09/24 06:00 [medline]
PHST- 2020/12/22 17:10 [entrez]
AID - 10.1021/acs.chemrestox.0c00294 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2021 Feb 15;34(2):365-384. doi: 10.1021/acs.chemrestox.0c00294. 
      Epub 2020 Dec 22.