Arylthioindoles (ATIs) are potent tubulin assembly inhibitors that bind to the colchicine site on beta-tubulin close to its interface with alpha-tubulin .1-4 In order to investigate the structural basis of the SAR that emerged from the biological results, we carried out docking and molecular dynamics studies. First generation ATIs (R1 = COOR) established one hydrogen bond between the carbonyl group of the ester function and beta:Lys352 and another between the NH group and alpha:Thr179 into the colchicine site of tubulin.1,2 Despite the absence of the ester moiety, binding to beta-tubulin of the second generation ATIs (R1 = H) involved formation of a hydrogen bond between the NH group and :Thr179 and positioning of the trimethoxyphenyl group in a hydrophobic pocket close to beta:Cys241.3 Replacement of the sulfur atom with a methylene or carbonyl moiety led to similar docking pose as reported for first and second generation ATIs.4 Molecular dynamics simulations confirmed stable interactions between ATIs and tubulin for proposed binding modes. References [1]. J. Med. Chem. 2004, 47, 6120-6123. [2]. J. Med. Chem. 2006, 49, 947-954. [3]. J. Med. Chem. 2007, 50, 2865-2874. [4]. J. Med. Chem. 2009, accepted.
Molecular modeling studies of arylthioindoles and related bioisosteres, potent inhibitors of tubulin polymerization / LA REGINA, Giuseppe; Coluccia, Antonio; Gatti, Valerio; Saletti, R.; Brancale, A.; Novellino, E.; Silvestri, Romano. - (2009). (Intervento presentato al convegno VI European Workshop in Drug Design tenutosi a Siena, Italy).
Molecular modeling studies of arylthioindoles and related bioisosteres, potent inhibitors of tubulin polymerization
LA REGINA, GIUSEPPE
;COLUCCIA, Antonio;GATTI, VALERIO;SILVESTRI, Romano
2009
Abstract
Arylthioindoles (ATIs) are potent tubulin assembly inhibitors that bind to the colchicine site on beta-tubulin close to its interface with alpha-tubulin .1-4 In order to investigate the structural basis of the SAR that emerged from the biological results, we carried out docking and molecular dynamics studies. First generation ATIs (R1 = COOR) established one hydrogen bond between the carbonyl group of the ester function and beta:Lys352 and another between the NH group and alpha:Thr179 into the colchicine site of tubulin.1,2 Despite the absence of the ester moiety, binding to beta-tubulin of the second generation ATIs (R1 = H) involved formation of a hydrogen bond between the NH group and :Thr179 and positioning of the trimethoxyphenyl group in a hydrophobic pocket close to beta:Cys241.3 Replacement of the sulfur atom with a methylene or carbonyl moiety led to similar docking pose as reported for first and second generation ATIs.4 Molecular dynamics simulations confirmed stable interactions between ATIs and tubulin for proposed binding modes. References [1]. J. Med. Chem. 2004, 47, 6120-6123. [2]. J. Med. Chem. 2006, 49, 947-954. [3]. J. Med. Chem. 2007, 50, 2865-2874. [4]. J. Med. Chem. 2009, accepted.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
