A paradigm for drug discovery employing encoded combinatorial libraries.

Burbaum, Jonathan J.; Ohlmeyer, Michael; Reader, John; Henderson, Ian; Dillard, Lawrence W.; Li, Ge; Randle, Troy; Sigal, Nolan H.; Chelsky, Daniel; Baldwin, John J.

doi:10.1073/pnas.92.13.6027

Cited by 94 publications

(47 citation statements)

References 19 publications

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“…These compounds were generally very effective CA I and CA II inhibitors, but were not investigated-as far as we know-for their antiglaucoma properties. Similar derivatives were also reported by Burbaum et al 65 (derivatives of type 59), Antonarolli et al 66 (compound 60) and Jayaweera et al 67 -derivatives 61-63. Except for 60 (with weak IOP lowering properties 66 ) and 61, 62 (stated to be active, but no quantitative data provided in Ref.…”

Section: The ''Tail'' Approachsupporting

confidence: 73%

Carbonic anhydrase inhibitors

Supuran

Scozzafava

Casini

2002

Medicinal Research Reviews

1,417

839

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Section: The ''Tail'' Approachsupporting

confidence: 73%

Carbonic anhydrase inhibitors

Supuran

Scozzafava

Casini

2002

Medicinal Research Reviews

1,417

839

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“…the fused aromatic ring), both experimental and modeling data derived from this structure may illuminate new structure-activity relationships that may be relevant to the design of pharmaceutically useful CAII inhibitors (Maren, 1987). Notably, previous structure-activity relationships indicate that an ortho substituent on an arylsulfonamide moiety compromises enzyme-inhibitor affinity (Burbaum et al, 1995;Vedani and Meyer, 1984;Hansch et al, 1985;Menziani et al, 1989); the three-dimensional structure of the CAII-dansylamide complex suggests that this is not an absolute relationship if alternate conformations of Leu-198 and zinc-bound sulfonamide are attainable. Holding zinc-bound sulfonamide fixed in its experimentally observed position, the naphthyl group of dansylamide can be rotated about the C-S bond into an alternate conformation, which does not suffer from severe steric clashes and engages in van der Waals interactions with (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unexpected Binding Mode of the Sulfonamide Fluorophore 5-Dimethylamino-1-naphthalene Sulfonamide to Human Carbonic Anhydrase II

Nair¹,

Elbaum²,

Christianson³

1996

Journal of Biological Chemistry

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The three-dimensional structure of human carbonic anhydrase II (CAII) complexed with the sulfonamide fluorophore 5-dimethylamino-1-naphthalene sulfonamide (dansylamide) has been determined to 2.1-Å resolution by x-ray crystallographic methods. Unlike other arylsulfonamide inhibitors of CAII, the naphthyl ring of dansylamide binds in a hydrophobic pocket in the active site, making van der Waals contacts with Val-121, Phe-131, Val-143, Leu-198, and Trp-209. Interestingly, a conformational change of Leu-198 is required to accommodate dansylamide binding, which rationalizes the enhanced dansylamide affinity measured for certain Sensors based upon biological macromolecules are increasingly used for the selective detection of numerous chemical entities, including the detection of trace quantities of metal ions. The advantages of metalloprotein-based biosensors over classical fluorometric chemical indicators for such applications include greater recognition and affinity for the target metal ion, exquisite discrimination among transition metals, and kinetically rapid biosensor-analyte association and dissociation. Recently, Thompson and Jones (1993) have exploited the selective recognition of zinc by the metalloenzyme carbonic anhydrase II (CAII) 1 in the design of an enzyme-based zinc biosensor. The physical basis of this sensor is the binding of zinc to the CAII apoenzyme, followed by binding of the fluorophore inhibitor 5-dimethylamino-1-naphthalene sulfonamide (dansylamide, K d ϭ 0.93 M (Nair et al., 1995); see Fig. 1) to the zinccontaining CAII holoenzyme. This leads to a titratable change in the fluorescence emission wavelength and intensity (Chen and Kernohan, 1967); nanomolar concentrations of zinc can be detected and quantified by ratiometric methods by measuring the emission of free dansylamide at 580 nm and the emission of bound dansylamide at 470 nm when excited at 290 nm.The zinc ion of CAII resides at the base of a 15-Å deep cleft, where it is liganded by the imidazole side chains of His-94, His-96, and His-119 (Håkansson et al., 1992). Hydroxide ion, which is the catalytic nucleophile in the CO 2 hydration mechanism, completes a tetrahedral metal coordination polyhedron. Zinc-bound hydroxide donates a hydrogen bond to the hydroxyl group of Thr-199, which in turn donates a hydrogen bond to Glu-106 (Eriksson et al., 1986, 1988aHåkansson et al., 1992). The binding of sulfonamide inhibitors displaces zinc-bound hydroxide and maintains the tetrahedral metal coordination polyhedron by the coordination of an ionized sulfonamide NH group, which also maintains the hydrogen bond interaction with Thr-199 (e.g. see Eriksson et al. (1988b) and Vidgren et al.

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“…543 Burbaum et al used BCA II as the model enzyme to test the concept of encoded combinatorial libraries for small-molecule drug discovery due to the synthetic accessibility of arylsulfonamides and the extensive structural and medicinal knowledge of their interactions with BCA II. 506 They constructed two libraries based on benzenesulfonamide-one containing 1143 compounds and the other containing 6727 compounds. Using the dansylamide (DNSA, 133) displacement assay to measure binding affinity, their technique identified two inhibitors, one of which (108) had a K d of 4 nM.…”

Section: Combinatorial Approaches To Ligandmentioning

confidence: 99%

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

et al. 2008

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I. Introduction to Carbonic Anhydrase (CA) and to the Review 948 1. Introduction: Overview of CA as a Model 948 1.1. Value of Models 950 1.2. Objectives and Scope of the Review 950 2. Overview of Enzymatic Activity 950 3. Medical Relevance 951 II. Structure and Structure−Function Relationships of CA 953 4. Global and Active-Site Structure 953 4.1. Structure of Isoforms 953 4.2. Isolation and Purification 954 4.3. Crystallization 954 4.4. Structures Determined by X-ray Crystallography and NMR 955 4.4.1. Structures Determined by X-ray Crystallography 955 4.4.2. Structure Determined by NMR 955 4.5. Global Structural Features 963 4.6. Structure of the Binding Cavity 964 4.7. Zn II -Bound Water 965 5. Metalloenzyme Variants 966 6. Structure−Function Relationships in the Catalytic Active Site of CA 968 6.1. Effects of Ligands Directly Bound to Zn II 968 6.2. Effects of Indirect Ligands 969 7. Physical-Organic Models of the Active Site of CA 969 III. Using CA as a Model to Study Protein−Ligand Binding 970 8. Assays for Measuring Thermodynamic and Kinetic Parameters for Binding of Substrates and Inhibitors 970 8.1. Overview 970 8.

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A paradigm for drug discovery employing encoded combinatorial libraries.

Abstract: Very

Cited by 94 publications

References 19 publications

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors

Unexpected Binding Mode of the Sulfonamide Fluorophore 5-Dimethylamino-1-naphthalene Sulfonamide to Human Carbonic Anhydrase II

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

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