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Cover Picture: Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey (ChemMedChem 12/2006)
Author(s) -
Hanessian Stephen
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Reports
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200690043
Subject(s) - chemistry , dihedral angle , lipophilicity , chlorine atom , stereochemistry , crystallography , hydrogen bond , organic chemistry , molecule , medicinal chemistry
The cover picture shows the cyanobacterial linear peptides dysinosin A (RH) and chlorodysinosin A (RCl), members of the aeruginosin family of cyanobacterial linear peptides. Their structures and absolute configurations were determined by total synthesis and X‐ray co‐crystallization with the enzyme thrombin. The presence of one chlorine atom in the D ‐leucine residue of chlorodysinosin A remarkably increases the inhibition potency against thrombin and Factor VIIa relative to dysinosin A. Molecular mechanics simulations starting from the bound conformations of dysinosin A and its chloro analogue suggest a more restricted sampling of conformations for the latter around the χ 1 dihedral angle. The chlorine atom in chlorodysinosin A may also contribute to lipophilicity, leading to a better fit in the hydrophobic S 3 pocket, as illustrated in the partial X‐ray co‐crystal structure. The background of the picture shows Lizard Island in North Queensland, Australia, where dysinosin A was isolated from the Dysideidae family of marine sponges. For details, see the Review by S. Hanessian on p. 1300 ff.