Hit validation and lead optimization in early drug discovery using Isothermal Titration Calorimetry

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00:00:00 From hit to lead - accelerate early drug discovery with ITC
00:02:16 MicroCal iTC200 and MicroCal Auto-iTC200
00:02:56 Why Microcalorimetry?
00:04:17 All binding parameters in a single experiment
00:05:53 Microcalorimetry provides a total picture of binding energetics
00:07:55 Same affinity, different energetics
00:10:13 With ITC you can…
00:11:55 Protein quality/assay development
00:13:22 ITC applications in drug discovery
00:13:47 MicroCal Auto-iTC200 in hit validation
00:14:15 Confirm binding-compare to IC50
00:14:55 Confirm binding-false positives
00:15:37 MicroCal ITC systems confirm 1 to 1 binding to active site
00:16:56 Hit validation of fragment screen against Vsp34: A drug discovery program to reduce resistance to cancer drugsCollaborative work between Sprint Biosciences and MicroCal Products
00:17:22 Overview
00:19:17 Vps34 Fragment-based screening: quality in focus
00:20:37 85% of validated ligands gave co-crystal structures
00:21:22 Summary – ITC for hit validation
00:21:58 MicroCal Auto-iTC200 in MOA
00:22:11 Revealing kinase inhibitors mechanisms: ITC leads the wayApplication note Geoff Holdgate
00:22:24 MOA: ATP competitive binding
00:24:04 MOA: ATP uncompetitive binding
00:24:39 Inhibitor binding to the homodimer Caspase-3
00:25:50 Summary - ITC for MoA studies
00:26:13 MicroCal Auto-iTC200 in lead optimization
00:27:02 SAR by ITC
00:28:35 Support structure based lead optimization programs
00:29:06 Optimizing diaminopyrimidine renin inhibitors aided by ITC and structural data Abstracted from Ron Sarver, Current Trends in Microcalorimetry
00:29:14 The binding orientation of lead compound from high throughput screening
00:30:04 Data suggests substituting aryl-benzamide with aryl-sulfonamide to improve H-bonds
00:32:36 Renin inhibitor affinity improved 45X from initial 3.6 μM lead to 79nM
00:33:53 The best drugs have more enthalpic binding
00:35:48 Summary - ITC in lead optimization
00:36:37 Summary
00:38:01 Thank You!
00:45:26 Contact Information

Isothermal Titration Calorimetry (ITC) is a label free technique for measuring the affinity, stoichiometry and thermodynamics of an interaction. It requires minimal sample preparation and delivers high quality affinity data in a fast, unattended experiment. The high quality of the data and the ease of use of the instrument has resulted in a wide spread adoption of the technique in early drug discovery programs. This presentation includes a number of examples where ITC has been used in hit validation, lead optimization and mechanism of action studies as well as a protein quality monitor in assay development laboratories.