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2015 ; 58
(17
): 7076-87
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An Aggregation Advisor for Ligand Discovery
#MMPMID26295373
Irwin JJ
; Duan D
; Torosyan H
; Doak AK
; Ziebart KT
; Sterling T
; Tumanian G
; Shoichet BK
J Med Chem
2015[Sep]; 58
(17
): 7076-87
PMID26295373
show ga
Colloidal aggregation of organic molecules is the dominant mechanism for
artifactual inhibition of proteins, and controls against it are widely deployed.
Notwithstanding an increasingly detailed understanding of this phenomenon, a
method to reliably predict aggregation has remained elusive. Correspondingly,
active molecules that act via aggregation continue to be found in early discovery
campaigns and remain common in the literature. Over the past decade, over 12
thousand aggregating organic molecules have been identified, potentially enabling
a precedent-based approach to match known aggregators with new molecules that may
be expected to aggregate and lead to artifacts. We investigate an approach that
uses lipophilicity, affinity, and similarity to known aggregators to advise on
the likelihood that a candidate compound is an aggregator. In prospective
experimental testing, five of seven new molecules with Tanimoto coefficients
(Tc's) between 0.95 and 0.99 to known aggregators aggregated at relevant
concentrations. Ten of 19 with Tc's between 0.94 and 0.90 and three of seven with
Tc's between 0.89 and 0.85 also aggregated. Another three of the predicted
compounds aggregated at higher concentrations. This method finds that 61?827 or
5.1% of the ligands acting in the 0.1 to 10 ?M range in the medicinal chemistry
literature are at least 85% similar to a known aggregator with these physical
properties and may aggregate at relevant concentrations. Intriguingly, only 0.73%
of all drug-like commercially available compounds resemble the known aggregators,
suggesting that colloidal aggregators are enriched in the literature. As a
percentage of the literature, aggregator-like compounds have increased 9-fold
since 1995, partly reflecting the advent of high-throughput and virtual screens
against molecular targets. Emerging from this study is an aggregator advisor
database and tool ( http://advisor.bkslab.org ), free to the community, that may
help distinguish between fruitful and artifactual screening hits acting by this
mechanism.
free
free
free
