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Foye's Principles of Medicinal Chemistry (Lemke, Foye's Principles of Medicinal Chemistry) PDF

2293 Pages·2007·65.13 MB·English
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Preview Foye's Principles of Medicinal Chemistry (Lemke, Foye's Principles of Medicinal Chemistry)

http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Color Section Fig. 3.1. Visualization of a drug molecule N-(4-hydroxy- phenyl)-acetamide (Tylenol or acetaminophen) computerized with different levels of graphic representations. (A) Molecular structure of the drug Tylenol. (B) Ball-stick model showing atomic positions and types. (C) Ball-stick model with van der Waals dot surfaces. (D) Space-fil led model showing van der Walls radii of the oxygen, nitrogen, and carbon atoms. (E) Solvent accessible surface model (sol id) (solvent radius, 1.4Å). (See black and white image.) Fig. 3.3. Graphic visualization of molecular orbital surface 1 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... HOMO/LUMO calculation for the drug molecule acetaminophen. (See black and white image.) Fig. 3.7. Nuclear magnetic resonance NOE-constrained molecular dynamics/molecular mechanics structure calculation of (A) the polypeptides CB2I298-K319; (B) the amino acid backbone superimposition of 10 low-energy conformers; (C) the cyl inder representation with a turn at the fifth residue, arginine; (d) and the ribbon display of the two helical segments, showing a curve side chain of Arg302 forming a salt bridge (green l ine) with Glu305. (See black and white image.) 2 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Fig. 3.8. A workflow of in sil ico virtual screening process: receptor-based and l igand-based approaches. (See black and white image.) Fig. 3.9. Three-dimensional G protein–coupled CB2 receptor structure (right) constructed by homology and multiple sequence al ignment 3 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... method (left), including the seven transmembrane helices (cyl inders, I–VII) and loop regions (ribbons). (From Xie XQ, Chen JZ, Bil l ings EM. 3D structural model of the G protein–coupled cannabinoid CB2 receptor. Proteins: Structure, Function, and Genetics 2003;53:307–319; with permission.) (See black and white image.) Fig. 3.10. MOLCAD-predicted CB2-binding pocket surrounded by active amino acid residues, showing an amphipathic contour, hydrophil ic center (blue), and hydrophobic cleft (brown). The site-directed mutagenesis– 4 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... detected binding residues are color-coded in terms of their distance to the pocket (magenta > yel low > green > blue) as the interaction weakens. (See black and white image.) Fig. 3.11. CoMFA contour maps for arylpyrazole antagonists of cannabinoid receptor subtypes CB1 (A) and CB2 (B). Sterical ly favored areas (contribution level, 80%) are shown in green. Sterical ly unfavored areas (contribution level, 20%) are shown in yel low, and positive- potential favored areas (contribution level, 80%) are shown in blue. Positive-potential unfavored areas (contribution level, 20%) are shown in red. Plots of the corresponding CoMFA-calculated and experimental values of binding affinity (given as pKi) of arylpyrazole compounds at CB1 (AA) and CB2 (BB) receptor, respectively are shown as well . (Adapted with permission from Chen J, Han X, Lan R, et al. 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach. J Med Chem 2006;49:625–636; with permission.) (See black and white image.) 5 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Fig. 17.4. Ribbon diagram of monomeric PDE4D2 (PDB 1PTW). 5′-AMP is shown as balls-and-sticks, whereas two divalent metal icons are shown as sol id spheres. (From Manallack DT, Hughes RA, Thompson PE. The next generation of phosphodiesterase inhibitors: structural clues to l igand and substrate selectivity of phosphodiesterases. J Med Chem 2005;48:3449–6342; with permission.) (See black and white image.) 6 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Fig. 17.5. Surface representation showing 5′-AMP in the nucleotide binding pocket of PDE4D2 (PDB 1PTW). 5′-AMP is shown as balls- and-sticks, while two divalent zinc icons are shown as sol id spheres. (From Manal lack DT, Hughes RA, Thompson PE. The next generation of phosphodiesterase inhibitors: structural clues to l igand and substrate selectivity of phosphodiesterases. J Med Chem 2005;48:3449–6342; with permission.) (See black and white image.) 7 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Fig. 17.7. Ribbon diagram of the active site of PDE4D2. The AMP phosphate group binds two divalent zinc icons and forms hydrogen bonds with His-160, Asp-201, and Asp-318. The adenine group of AMP adopts an anticonformation and orients toward the hydrophobic pocket made up of residues Tyr-159 (not shown), Leu-319, Asn-321, Thr-333, Ile-336, Gln-369, and Phe-372. It forms three hydrogen bonds with Gln-369 and Asn-321 and buttresses against Phe-372. The ribose of AMP has a C3′-endo puckering configuration and makes van der Waals contacts with residues His-160, Met-273, Asp-318, Leu-319, Ile-336, Phe-340, and Phe-372. (From Manallack DT, Hughes RA, Thompson PE. The next generation of phosphodiesterase inhibitors: structural clues to l igand and substrate selectivity of phosphodiesterases. J Med Chem 2005;48:3449–6342; with permission.) (See black and white image.) 8 of 9 11/5/2008 3:01 AM http://thepointeedition.lww.com/pt/re/9780781768795/bookContentPane_... Fig. 17.9. Overlay of sildenafil with 5′-GMP in the active site of PDE5. (From Matot I, Gozal Y. Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors. Chest 2004;125:644–651; with permission.) (See black and white image.) Fig. 17.11. Overlay of (R,S)-rol ipram with 5′-AMP in the active site of PDE4D. (From Maurice DH, Palmer D, Til ley DG, et al . Cycl ic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 2003;64:533–546; with permission.) (See black and white image.) 9 of 9 11/5/2008 3:01 AM

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