Is there a link between selectivity and binding thermodynamics profiles?

Tarcsay, Ákos; Keserü, György M.

doi:10.1016/j.drudis.2014.09.014

Cited by 41 publications

(23 citation statements)

References 45 publications

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“…And third, the thermodynamic data demonstrate that the binding of tropolones to CapF is driven by favorable changes of enthalpy. It is generally considered that among compounds of fragment-size, exothermic binding is an important advantage for ligand optimization because enthalpic binding accomplishes highly oriented interactions making these candidates less promiscuous binders2728.…”

Section: Discussionmentioning

confidence: 99%

Discovery and characterization of natural tropolones as inhibitors of the antibacterial target CapF from Staphylococcus aureus

Nakano

Chigira

Miyafusa

et al. 2015

Sci Rep

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The rapid spread of antibiotic-resistance among pathogenic bacteria poses a serious risk for public health. The search for novel therapeutic strategies and antimicrobial compounds is needed to ameliorate this menace. The bifunctional metalloenzyme CapF is an antibacterial target produced by certain pathogenic bacteria essential in the biosynthetic route of capsular polysaccharide, a mucous layer on the surface of bacterium that facilitates immune evasion and infection. We report the first inhibitor of CapF from Staphylococcus aureus, which was identified by employing fragment-based methodologies. The hit compound 3-isopropenyl-tropolone inhibits the first reaction catalyzed by CapF, disrupting the synthesis of a key precursor of capsular polysaccharide. Isothermal titration calorimetry demonstrates that 3-isopropenyl-tropolone binds tightly (KD = 27 ± 7 μM) to the cupin domain of CapF. In addition, the crystal structure of the enzyme-inhibitor complex shows that the compound engages the essential Zn2+ ion necessary for the first reaction catalyzed by the enzyme, explaining its inhibitory effect. Moreover, the tropolone compound alters the coordination sphere of the metal, leading to the overall destabilization of the enzyme. We propose 3-isopropenyl-tropolone as a precursor to develop stronger inhibitors for this family of enzymes to impair the synthesis of capsular polysaccharide in Staphylococcus aureus.

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Section: Discussionmentioning

confidence: 99%

Discovery and characterization of natural tropolones as inhibitors of the antibacterial target CapF from Staphylococcus aureus

Nakano

Chigira

Miyafusa

et al. 2015

Sci Rep

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“…It is important to note that in agreement to our observation [14] significant improvement in binding enthalpy was achieved in the early phase of the optimization with less complex compounds. Furthermore, the Novartis tankyrase dataset with PARP1 and PARP2 selectivity data supports the hypothesis that enthalpic compounds are generally more selective [11]. Although the thermodynamic profiles of key compounds were recorded the authors used lipophilic efficiency, particularly LLE as the major design tool in this optimization.…”

Section:  Tankyrase Inhibitorsmentioning

confidence: 93%

“…Freire and coworkers showed that enthalpic compounds have higher chance being selective against off-targets [10]. Compounds binding their targets with higher entropy contributions tend to hit more off-targets compared to those ligands that had enthalpically-driven thermodynamics profile [11]. Thermodynamic investigations might therefore help both in the understanding of interconnecting relations between molecular properties and also in controlling them.…”

Section: Drug Discovery Optimizations and Molecular Obesitymentioning

confidence: 99%

The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

Ferenczy

Keserü

2015

Future Med. Chem.

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Background: Ligand binding thermodynamics has been attracted considerable interest in the past decade owing to the recognized relation between binding thermodynamic profile and the physicochemical and druglike properties of compounds. Discussion: • Affinity improvements in drug discovery optimizations can be either enthalpically or entropically driven. In this review the relation between optimization strategies and ligand properties are presented based on the structural and thermodynamic analysis of ligand-protein complex formation. Conclusions: The control of the binding thermodynamic profile is beneficial for the balanced affinity and physicochemical properties of drug candidates and early phase optimization gives more opportunity to this control.

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“…Nevertheless, if we want to understand and manipulate biological systems, e.g. in the design of potent medicinal drugs or more efficient enzymes with new reactivity, it is necessary to understand and exploit both enthalpic and entropic effects, [2][3][4] especially as it is normally observed that improvements in enthalpy are counteracted (compensated) by adverse entropy effects, and vice versa. 3,5 The standard method to measure entropy changes is isothermal titration calorimetry (ITC).…”

Section: Introductionmentioning

confidence: 99%