Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: Binding of phosphonamidate to the S1'-pocket of thermolysin

Englert, L.; Biela, Adam; Zayed, Mohamed F.; Heine, A.; Hangauer, David; Klebe, G.

doi:10.1016/j.bbagen.2010.06.009

Cited by 80 publications

(88 citation statements)

References 45 publications

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“…22 Owing to the complex roles which water can perform in protein binding sites, 23 the reliable incorporation of water molecules into computational drug design is of critical importance. Indeed, studies have shown that incorporating water molecules into docking and virtual screening approaches can dramatically improve the predictions formed when analysing the predicted poses.…”

Section: Studies By Setny Baron and Mccammonmentioning

confidence: 99%

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Bodnarchuk

Viner

Michel

et al. 2014

J. Chem. Inf. Model.

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Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding.As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies; Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC) and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be * To whom correspondence should be addressed † University of Southampton ‡ Syngenta ¶ University of Edinburgh 1 calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design.

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Section: Studies By Setny Baron and Mccammonmentioning

confidence: 99%

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Bodnarchuk

Viner

Michel

et al. 2014

J. Chem. Inf. Model.

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“…The crystal structures complexes with small molecules show that upon binding, the zinc coordinating water molecule is replaced by one or two oxygen atoms from the inhibitor forming a monodentate or bidentate arrangements with the catalytic zinc ion [17][18][19]. The X-ray complexes also show that the overall geometry of the binding pocket can be divided into three subpockets, the S1 ' -, S2 ' -, and S1-subpockets [4,20]. The S1 ' -subpocket is the main binding region for substrate recognition, and accommodates specifically hydrophobic amino acids of the substrate, both for thermolysin and pseudolysin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Sjøli

Nuti

Camodeca

et al. 2016

European Journal of Medicinal Chemistry

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Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from grampositive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S2 ' subpocket by an aromatic group is favourable for strong interactions with pseudolysin.

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“…[4][5][6] Many studies have investigated the role of water in protein-ligand interactions by examining the association of model proteins with sets of structurally varied ligands. [7][8][9][10][11][12][13][14][15] Such studies have revealed how the thermodynamic influence of water can differ between binding processes (e.g., the entropy-driven association of nonpolar ligands with the "well-hydrated" S3/4 pocket of thrombin, [7] or the enthalpy-driven binding of nonpolar molecules to the "poorly hydrated" cavity of mouse major urinary protein [8] ); they have not, however, illuminated the thermodynamic consequences brought about by systematic changes in the organization of water within a single pocket. An examination, thus focused, could reveal how different hydration/rehydration processes alter the thermodynamic mechanisms by which-and overall affinities with which-proteins and ligands associate.…”

Section: Introductionmentioning

confidence: 99%

Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

Fox

Kang

Sastry³

et al. 2017

Angew Chem Int Ed

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This study uses mutants of human carbonic anhydrase (HCAII) to examine how changes in the organization of water within a binding pocket can alter the thermodynamics of protein–ligand association. Results from calorimetric, crystallographic, and theoretical analyses suggest that most mutations strengthen networks of water‐mediated hydrogen bonds and reduce binding affinity by increasing the enthalpic cost and, to a lesser extent, the entropic benefit of rearranging those networks during binding. The organization of water within a binding pocket can thus determine whether the hydrophobic interactions in which it engages are enthalpy‐driven or entropy‐driven. Our findings highlight a possible asymmetry in protein–ligand association by suggesting that, within the confines of the binding pocket of HCAII, binding events associated with enthalpically favorable rearrangements of water are stronger than those associated with entropically favorable ones.

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Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: Binding of phosphonamidate to the S1'-pocket of thermolysin

Cited by 80 publications

References 45 publications

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

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