Homology modeling and calculation of the cobalt cluster charges of the Encephazlitozoon cuniculi methionine aminopeptidase, a potential target for drug design.
Fumagillin is a potent anti-angiogenic drug used in cancer treatments. It is also one of the few molecules active against the Enterocytozoon and Encephalitozoon parasites responsible for various clinical syndromes in HIV-infected or immunosuppressive treated patients. Its toxicity, however, makes desirable the design of more specific molecules. The fumagillin target, as anti-angiogenic agent, is the methionine aminopeptidase, an ubiquitous metallo-enzyme responsible for the removing of the N-terminal methionine in nascent proteins. By analogy, it has been proposed that this enzyme could also be the target in the parasites. As a first approach to verify this and to determine if it would be possible to design a more specific derivative, we have built a homology model of the E. cuniculi aminopeptidase. The charges of the two cobalt ions present in the active site and of the side-chains involved in their binding were computed using ab-initio methods. A preliminary comparison of the interactions of the fumagillin and of a related compound, the TNP-470, with both the human and the parasitic enzymes strongly support the hypothesis that the parasitic aminopeptidase is indeed the target of the fumagillin. It also suggests that the TNP-470 interact identically with both enzymes while there could be small differences in case of the fumagillin.
Bontems
François
F
Equipe ICSN-RMN, Ecole Polytechnique, F91128 Palaiseau France. francois.bontems@polytechnique.fr
le Floch
Pascal
P
Duffieux
Francis
F
Biderre
Corinne
C
Peyret
Pierre
P
Lallemand
Jean-Yves
JY
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D003035:Cobalt / Q000737:chemistry*; D003510:Cyclohexanes; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D063208:Methionyl Aminopeptidases; D021861:Microsporidia, Unclassified / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011485:Protein Binding; D016415:Sequence Alignment; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055672:Static Electricity
D020533:Angiogenesis Inhibitors; D000981:Antiprotozoal Agents; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; D003035:Cobalt; C026211:fumagillin; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol