ABSTRACT
Microtubules (MTs), which are highly dynamic assemblies of the protein tubulin, play important and diverse roles in eukaryotic cells. MT dynamics are regulated during the cell cycle by interacting with a large number of endogenous cellular regulators. In addition, many anti-tumour drugs and natural ligands that interact directly with tubulin are able to either stabilise or destabilise MTs and to disrupt the normal dynamics. Herein, we compare the structures of tubulin when complexed with different ligands in order to analyse: (i) various binding-sites of the protein and different positions of ligands within the microtubule (ii) the diverse effect on the microtubule dynamics. The structures and data given are essential for understanding tubulin-ligand interactions and their influence on the regulation of the microtubule system.
Subject(s)
Antineoplastic Agents/pharmacology , Microtubules/drug effects , Tubulin Modulators/pharmacology , Tubulin/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Crystallography, X-Ray , Drug Design , Humans , Ligands , Magnetic Resonance Spectroscopy , Microtubules/chemistry , Microtubules/metabolism , Models, Molecular , Molecular Structure , Protein Conformation , Protein Structure, Tertiary , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/metabolismABSTRACT
Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signaling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions.
Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Neoplasms/enzymology , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-fes/antagonists & inhibitors , Proto-Oncogene Proteins c-fes/metabolism , Animals , Antineoplastic Agents/pharmacology , Humans , Models, Molecular , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-fes/chemistryABSTRACT
In the last twenty years the efforts to design and optimize new drugs have been based on the three dimensional structure of the selected target proteins. In this regard, useful information has been achieved mainly by protein crystallography, which has recently turned from a low into a high-throughput process thanks to the improvement in robot technologies, automation procedure and the use of synchrotron radiation facilities [1-3]. This review examines the impact of Structure Based Drug Design (SBDD) on the discovery of ligands as the selective estrogen receptor modulators (SERMs) of the Estrogen Receptor (ER)α, which is involved in the regulation of several physiological and pathological processes.
