The taxol pharmacophore and the T-taxol bridging principle.
Different approaches to developing an accurate model of the binding conformation of paclitaxel (Taxol, PTX) on beta-tubulin are discussed. Electron crystallography, molecular modeling, NMR and synthetic studies all point to the T-Taxol conformation as the bioactive form. The range of molecular designs represented by synthetic taxoids prepared to test the latter, with an emphasis on internally bridged analogs, is summarized. Key implications and conclusions derived from the retrospective are presented.
Kingston
David G I
DG
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Bane
Susan
S
Snyder
James P
JP
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D003461:Crystallography; D015195:Drug Design; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D014404:Tubulin; D017239:Paclitaxel