In spite of increasing activity in the synthesis of gold(I) compounds for pharmacological purposes there is still some divergence of opinion in determining their mechanism of action and their possible molecular target. It is generally accepted that gold compounds act as multi-target drugs and the proposed mechanisms mainly involve enzymes. Some pyrazolyl and imidazolyl gold(I) phosphane complexes synthesized by us have shown anticancer properties and they successfully inhibited seleno-dependent enzymes such as thioredoxine reductase and glutathione peroxidase.[1] DHFR is an important enzyme mainly involved in the synthesis of pyrimidine and thymine basilar for the DNA replication and hence the cell proliferation.[2] Despite its fundamental importance in the cell’s metabolism this enzyme has never been tested as molecular target for gold(I) compounds. Methotrexate is a well-known inhibitor of DHFR and methotrexate and gold(I) complexes have a common history in the treatment of certain diseases such as psoriasis, rheumatoid arthritis and other autoimmune diseases. As a prosecution of an ongoing study about the action of gold(I) azolate phosphane complexes on the regard of the inhibition of DHFR, computational molecular docking studies have been led. They suggest that the compound 4,5-dicyanoimidazolate-AuPPh3 binds to a site of DHFR located in proximity of the nicotinamide moiety of NADP+ (Figure). Moreover, the studies suggest that the site of 4,5-dicyanoimidazolate-AuPPh3 partially overlaps with the methotrexate, indicating that the binding of the two molecules may be mutually exclusive. These results support our kinetic data showing an interaction between pyrazolyl and imidazolyl gold(I) phosphane complexes and the catalytic site of DHFR. Figure. DHFR in complex with 4,5-ImCl2N-AuPPh3 and NADP+ References [1] R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307 [2] J.R. Schnell, H.J. Dyson, P.E. Wright. Annu. Rev. Biophys. Biomol. Struct., 2004, 33, 119–140.

Computational studies on inhibition of DHFR by gold(I) complexes.

GALASSI, Rossana;BURINI, Alfredo;COSTANZI, Stefano;PUCCIARELLI, Stefania
2013-01-01

Abstract

In spite of increasing activity in the synthesis of gold(I) compounds for pharmacological purposes there is still some divergence of opinion in determining their mechanism of action and their possible molecular target. It is generally accepted that gold compounds act as multi-target drugs and the proposed mechanisms mainly involve enzymes. Some pyrazolyl and imidazolyl gold(I) phosphane complexes synthesized by us have shown anticancer properties and they successfully inhibited seleno-dependent enzymes such as thioredoxine reductase and glutathione peroxidase.[1] DHFR is an important enzyme mainly involved in the synthesis of pyrimidine and thymine basilar for the DNA replication and hence the cell proliferation.[2] Despite its fundamental importance in the cell’s metabolism this enzyme has never been tested as molecular target for gold(I) compounds. Methotrexate is a well-known inhibitor of DHFR and methotrexate and gold(I) complexes have a common history in the treatment of certain diseases such as psoriasis, rheumatoid arthritis and other autoimmune diseases. As a prosecution of an ongoing study about the action of gold(I) azolate phosphane complexes on the regard of the inhibition of DHFR, computational molecular docking studies have been led. They suggest that the compound 4,5-dicyanoimidazolate-AuPPh3 binds to a site of DHFR located in proximity of the nicotinamide moiety of NADP+ (Figure). Moreover, the studies suggest that the site of 4,5-dicyanoimidazolate-AuPPh3 partially overlaps with the methotrexate, indicating that the binding of the two molecules may be mutually exclusive. These results support our kinetic data showing an interaction between pyrazolyl and imidazolyl gold(I) phosphane complexes and the catalytic site of DHFR. Figure. DHFR in complex with 4,5-ImCl2N-AuPPh3 and NADP+ References [1] R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307 [2] J.R. Schnell, H.J. Dyson, P.E. Wright. Annu. Rev. Biophys. Biomol. Struct., 2004, 33, 119–140.
2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/287182
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