Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization

Davies, Nicholas; Browne, Helen; Davis, Ben; Drysdale, Martin J.; Foloppe, Nicolas; Geoffrey, Stephanie; Gibbons, Ben; Hart, Terance W.; Hubbard, Roderick E.; Jensen, Michael Rugaard; Mansell, Howard L.; Massey, Andrew; Matassova, Natalia; Moore, Jonathan D.; Murray, James B.; Pratt, Robert M.; Ray, Stuart C.; Robertson, Alan; Roughley, Stephen D.; Schoepfer, Joseph; Scriven, Kirsten; Simmonite, Heather; Stokes, Stephen; Surgenor, A.E.; Webb, Paul; Wood, Mike; Wright, Lisa; Brough, Paul A.

doi:10.1016/j.bmc.2012.08.050

Cited by 41 publications

(62 citation statements)

References 44 publications

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“…[34][35][36][37][38][39][40][41][42][43][44][45] Our simulation results suggest to keep only the structured water molecules that do not exchange with cosolvent in high-throughput docking campaigns. [34][35][36][37][38][39][40][41][42][43][44][45] Our simulation results suggest to keep only the structured water molecules that do not exchange with cosolvent in high-throughput docking campaigns.…”

Section: Introductionmentioning

confidence: 77%

Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent

et al. 2013

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Bromodomains are α-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2-5 ns, and 10-30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50-500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol.

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Section: Introductionmentioning

confidence: 77%

Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent

et al. 2013

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“…Davies and co-workerst argetedc rystallographic water molecules during the rational design of Hsp90 inhibitors ( Figure 3). [30] By changing the scaffold from purine (Davies-13b) to cyanopyrrolopyrimidine (Davies-15b), ac rystallographic water molecule bridging the interaction betweent he inhibitor and ASN51i sd isplaced, leadingt oagain in affinity by one order of magnitude.…”

Section: Protein-ligand Interactionsmentioning

confidence: 99%

“…In another example from the same series of Hsp90 inhibitors, [30] going from ac yanopyrrolopyrimidine (Davies-15a) to cyanopyrazolopyrimidine (Davies-16) led to ad rastic decrease in affinity by two orders of magnitude ( Figure 4). The authors suggest that the additional ring nitrogen atom engages in electronic repulsion with the water oxygen atom of HS2 and therefore leads to ad estabilization of the water network.…”

Section: Protein-ligand Interactionsmentioning

confidence: 99%

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

Wahl

Smieško

2018

ChemMedChem

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Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement.

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“…57,58 Their systematic displacement and the resulting consequences on ligand optimization have also been the subject of recent investigations. 59,60 These factors make Hsp90 an ideal test case to assess the predictions of IFST.…”

Section: Introductionmentioning

confidence: 99%

Combining Solvent Thermodynamic Profiles with Functionality Maps of the Hsp90 Binding Site to Predict the Displacement of Water Molecules

Haider

Huggins

2013

J. Chem. Inf. Model.

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Intermolecular interactions in the aqueous phase must compete with the interactions between the two binding partners and their solvating water molecules. In biological systems, water molecules in protein binding sites cluster at well-defined hydration sites and can form strong hydrogen-bonding interactions with backbone and side-chain atoms. Displacement of such water molecules is only favorable when the ligand can form strong compensating hydrogen bonds. Conversely, water molecules in hydrophobic regions of protein binding sites make only weak interactions, and the requirements for favorable displacement are less stringent. The propensity of water molecules for displacement can be identified using inhomogeneous fluid solvation theory (IFST), a statistical mechanical method that decomposes the solvation free energy of a solute into the contributions from different spatial regions and identifies potential binding hotspots. In this study, we employed IFST to study the displacement of water molecules from the ATP binding site of Hsp90, using a test set of 103 ligands. The predicted contribution of a hydration site to the hydration free energy was found to correlate well with the observed displacement. Additionally, we investigated if this correlation could be improved by using the energetic scores of favorable probe groups binding at the location of hydration sites, derived from a multiple copy simultaneous search (MCSS) method. The probe binding scores were not highly predictive of the observed displacement and did not improve the predictivity when used in combination with IFST-based hydration free energies. The results show that IFST alone can be used to reliably predict the observed displacement of water molecules in Hsp90. However, MCSS can augment IFST calculations by suggesting which functional groups should be used to replace highly displaceable water molecules. Such an approach could be very useful in improving the hit-to-lead process for new drug targets.

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Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization

Cited by 41 publications

References 44 publications

Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent

Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

Combining Solvent Thermodynamic Profiles with Functionality Maps of the Hsp90 Binding Site to Predict the Displacement of Water Molecules

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