| 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.