Thermodynamic profiling for fragment-based lead discovery and optimization

Figures & data

Figure 1. (a) Logarithmic plot of affinity (pK_d[max]) of the most potent ligands versus the number of heavy atoms (HAC). (b) Logarithmic plot of maximal favorable enthalpy (pK_H[max]; black round markers and straight line), and enthalpy of the most potent ligands (pK_H[pK_dmax]; red square markers and dashed line) versus the number of heavy atoms (HAC). Data were binned by ΔHAC = 3 and maximal values in each bin are shown. Based on data from Ref. [1].

Table 1. Reported experimental thermodynamic data for fragment–protein binding.

Target	Reference
Aldose Reductase	[66]
Beta-Glucosidase	[67]
Carbonic Anhydrase II	[36,42,68–70]
Enoyl-ACP Reductase	[71]
Farnesyl Diphosphate Synthase	[72]
Fatty Acid-Binding Protein	[73]
HSP90	[95]
Major Urinary Protein	[74–77]
MMP12	[93]
p38a	[78,79]
Pantothenate Synthetase	[80,81]
PIM-1 Kinase	[82]
PLP-dependent Transaminase	[83]
Polyandrocarpa Lectin	[84]
Protein Kinase A	[40]
Quinone Reductase 2	[85]
Ribonuclease A (Bovine)	[86]
Streptavidin	[87]
Thrombin	[37,88]
Thymidine Kinase	[89]
Transcriptional Regulator TtgR	[90]
Trypsin	[91,92]

Figure 2. (a) Optimization of MMP12 starting fragments using the fragment linking strategy. (b) Thermodynamic profiles of the starting fragments and the linked compound.

Figure 3. Optimization of the aromatic substituent in 3. The diagrams show the change of the thermodynamic quantities (ΔΔG: change in the binding free energy, ΔΔH: change in the binding enthalpy and −ΔTΔS: change in the binding entropy) along the optimization step.

Figure 4. Optimization of the sulfonamide nitrogen substituent in 3. The diagrams show the change of the thermodynamic quantities (ΔΔG: change in the binding free energy, ΔΔH: change in the binding enthalpy and −ΔTΔS: change in the binding entropy) along the optimization step.

Figure 5. Thermodynamic profiling of benzene sulfonamides on carbonic anhydrase.

Figure 6. Experimental binding modes of the 2-fluoro and 3-fluoro benzenesulfonamides at the binding site of human carbonic anhydrase. The 2-fluoro group points toward the hydrophilic wall (green) of the binding site. Contrary, the 3-fluoro group is located in a dominantly hydrophobic subpocket that is preferred by all the other halogens and also the nitriles used at different positions. Copyright: Royal Society of Chemistry [94] https://pubs.rsc.org/en/content/chapter/bk9781849733533-00023/978-1-84973-353-3.

Figure 7. Fragment growing applied for the optimization of 2-fluoro and 3-fluoro benzenesulfonamides against human carbonic anhydrase. The thermodynamic profile of the optimized 2-fluoro fragment preserved its enthalpic character.

Figure 8. Binding modes of compounds 9 and 10 obtained by X-ray crystallography. Structural waters are indicated by red spots.

Figure 9. Thermodynamic profiling of the fragments optimized against HSP90 at Astex.

Figure 10. Thermodynamic profiling of protein kinase A ligands obtained by systematic growing of the starting fragment (13).

Figure 11. Superposition of the crystal structures obtained for ligands 13–16. Orientations of sulfonamide oxygens indicate the different binding modes of 13 and 14 vs. 15 and 16. As a consequence, the Gly-rich loop was found in closed and open conformation, respectively.

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