Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone

Kung, Pei‐Pei; Sinnema, Piet-Jan; Richardson, Paul; Hickey, Michael J.; Gajiwala, K.S.; Wang, Fen; Huang, Buwen; McClellan, Guy A.; Wang, Jeff; Maegley, Karen A.; Bergqvist, Simon; Mehta, Pramod P.; Kania, Robert S.

doi:10.1016/j.bmcl.2011.04.130

Cited by 51 publications

(66 citation statements)

References 19 publications

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“…For consistency with previous studies, we refer to these water positions as W1, W2, W3, and W4. 60 The free energy of hydration sites corresponding to these water molecules, the best scoring probes (based on GBSA scores), and associated data are summarized in Table 5. These water molecules form a buried and tightly coordinated network of hydrogen bonds with the protein and/or ligand (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…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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“…PDB entry 3EKR (a co-crystal structure of 4-{[(2R)-2-(2-methylphenyl)pyrrolidin-1-yl]carbonyl}benzene-1,3-diol in complex with human Hsp90 with a resolution of 2Å) [21] was used for executing the docking studies. Four binding site waters (902, 903, 981 and 1026) were retained in the docking process as they provide key interactions required for stabilizing the ligand in the active site [20,[22][23][24]. This was followed by addition of hydrogens for the receptor and waters.…”

Section: Molecular Modeling Methodsmentioning

confidence: 99%

2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: Rational identification of a new anticancer lead

Gupta

Revathi

Mazaira

et al. 2015

Bioorganic Chemistry

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“…Not only do aryl methyl ketones participate as precursors to heterocycles, fragrances, and resins, 4 they have also been used as intermediates in the syntheses of a variety of drug candidates. 5 Several cross-coupling approaches to aryl methyl ketones have been reported, including carbonylative cross-couplings, 6,7 Heck reactions of enol ethers with subsequent hydrolysis, 8 and cross-coupling of α-alkoxyvinyl metal reagents with ensuing hydrolysis. 9,10 The most commonly used of these cross-couplings is highlighted in Figure 1.…”

mentioning

confidence: 99%

“…Stannane 1 can be coupled to aryl electrophiles to give ketone products 2 after hydrolysis of the intermediate coupling adduct. 5,10 …”

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confidence: 99%

Palladium-Catalyzed Acetylation of Arenes

Ramgren

Garg

2014

Org. Lett.

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Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone

Cited by 51 publications

References 19 publications

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

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

2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: Rational identification of a new anticancer lead

Palladium-Catalyzed Acetylation of Arenes

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