title: Dynamic Compound-Dependent Acoustic Transfer to Investigate Inhibitor Reversibility.
abstract: Automated mechanism of action studies are introducing the need for tailored compound delivery, which can be challenging for standard compound management procedures. Jump dilution assays investigating inhibitor reversibility require compound delivery at specific volumes to assay specific concentrations of 10 × IC50for each inhibitor. Creating custom-made source plates with unique compound concentrations to dispense a uniform single volume can be prohibitively slow. A broadly applicable tool that enables on-the fly dispensing of variable amounts of stock concentrations was developed using the Acoustic Transfer System (ATS). The Dynamic Transfer Modification Program (DTMP) is an integrated LabVIEW program used to automate customized volume transfers from each well based on compound identity within a given source plate. A jump dilution investigating the time-dependent inhibition of the enzyme dipeptidyl peptidase-4 (DPP4) with multiple inhibitors is described here to demonstrate the delivery of specific volumes of various compounds in a high-throughput manner. The ability to automate this process allows for the characterization of inhibitor reversibility earlier in the drug discovery process, resulting in better informed lead candidate selection.
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nothstein
authors.affiliation: 2 Hamilton College, Clinton, NY, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: MacColl
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Cassaday
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hermes
authors.affiliation: 1 Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Homsher
mesh_terms: D000162:Acoustics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D007201:Indicator Dilution Techniques; D020128:Inhibitory Concentration 50
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D018819:Dipeptidyl Peptidase 4
keywords: ATS (Acoustic Transfer System); DPP4 (dipeptidyl peptidase-4); inhibitor reversibility; jump dilution