Novel nikkomycin analogues: Inhibitors of the fungal cell wall biosynthesis enzyme chitin synthase

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 13, 2000, Pages 1451-1454

  Obi, Kikoh ^a   Uda, Jun Ichiro ^a   Iwase, Kazuhiko ^a   Sugimoto, Osamu ^a   Ebisu, Hiroyuki ^a   Matsuda, Akira ^b  

^a Kyorin Pharmaceutical Co L   (Japan)

^b HOKKAIDO UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFUNGAL AGENT; CHITIN SYNTHASE; DRUG ANALOG; ENZYME INHIBITOR;

ARTICLE; CANDIDA ALBICANS; CELL WALL; ENZYME INHIBITION; ENZYME INHIBITOR INTERACTION; NONHUMAN;

AMINO ACID SUBSTITUTION; AMINOGLYCOSIDES; ANTI-BACTERIAL AGENTS; BINDING SITES; CANDIDA; CELL WALL; CHITIN SYNTHASE; DRUG DESIGN; ENZYME INHIBITORS; MOLECULAR STRUCTURE; PROTEIN CONFORMATION;

CANDIDA ALBICANS;

EID: 0034601258     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00256-0     Document Type: Article

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13. Nikkomycin Z (NZ: 1) as reference compound was purchased from Calbiochem Inc.
14. 3′-endo in uridine ring conformation was used for the superposition. The structures of two Chs inhibitors (6q, 6u) were also generated through the conformational search. The lowest-energy structure was fully optimized each. During the CHARMm calculation, the dielectric constant for Chs was taken to be 10.0. The energy computations were performed on a Silicon Graphics 4D/35TG workstation. The resulting models were visualized on a Silicon Graphics O2/R5000 workstation. Flexible fitting: The flexible fitting NZ (1) to the template UDP-GlcNAc was performed such that the positions between the corresponding 5 atoms coincide with each other. The matched NZ (1) structure was within a 12 kcal/mol spread of energy from the global minimum. Two Chs inhibitors (6q, 6u) were also flexibly fitted to the template NZ (1) using the corresponding atoms. The structures of two inhibitors matched to NZ (1) were within a 10 kcal/mol spread of energy from the global minimum.
15. 2 version 3.5 (Molecular Simulations Inc., 9685 Scranton Road, San Diego, CA 92121-3752, USA). The receptor surface was colored brown to map the hydrophobic areas of the model and areas that were not hydrophobic were white.