Development, optimization and implementation of a centralized metabolic soft spot assay.
OBJECTIVE
High clearance is a commonly encountered issue in drug discovery. Here we present a centralized metabolic soft spot identification assay with adequate capacity and turnaround time to support the metabolic optimization needs of an entire discovery organization.


METHODS
An integrated quan/qual approach utilizing both an orthogonal sample-pooling methodology and software-assisted structure elucidation was developed to enable the assay. Major metabolic soft spots in liver microsomes (rodent and human) were generated in a batch mode, along with kinetics of parent disappearance and metabolite formation, typically within 1 week of incubation.


CONCLUSIONS
A centralized metabolic soft spot identification assay has been developed and has successfully impacted discovery project teams in mitigating instability and establishing potential structure-metabolism relationships.
Bristol-Myers Squibb R & D, SATT, 5 Research Parkway, Wallingford, CT 06492, USA.
Anthony A
AA
Paiva
Bristol-Myers Squibb R & D, PCO, 5 Research Parkway, Wallingford, CT 06492, USA.
Cheryl
C
Klakouski
Bristol-Myers Squibb R & D, SATT, 5 Research Parkway, Wallingford, CT 06492, USA.
Shu
S
Li
Bristol-Myers Squibb R & D, PCO, 5 Research Parkway, Wallingford, CT 06492, USA.
Benjamin M
BM
Johnson
Bristol-Myers Squibb R & D, PCO, 3551 Lawrenceville, Princeton, NJ 08648, USA.
Yue-Zhong
YZ
Shu
Bristol-Myers Squibb R & D, PCO, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA.|Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, CA 95134, USA.
Jonathan
J
Josephs
Bristol-Myers Squibb R & D, SATT, 5 Research Parkway, Wallingford, CT 06492, USA.
Tatyana
T
Zvyaga
Lead Molecular Design SL, Sant Cugat de Valles, Spain.
Ismael
I
Zamora
Bristol-Myers Squibb R & D, SATT, 5 Research Parkway, Wallingford, CT 06492, USA.
Wilson Z
WZ
Shou
D000818:Animals; D001681:Biological Assay; D002853:Chromatography, Liquid / Q000592:standards*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007700:Kinetics; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D012984:Software; D053719:Tandem Mass Spectrometry / Q000592:standards*
dual-concentration incubation; metabolic soft spot; metabolic stability; orthogonal sample pooling; software assisted data processing