METHODS

摘要

A method for selecting or designing a compound for modulating the activity of phosphoinositide dependent protein kinase 1 (PDKI), the method comprising the step of using molecular modelling means to select or design a compound that is predicted to interact with the protein kinase catalytic domain of PDKI, wherein a three-dimensional structure of at least a part of the protein kinase catalytic domain of PDK1 is compared with a three-dimensional structure of a compound, and a compound that is predicted to interact with the said protein kinase catalytic domain is selected, wherein the three-dimensional structure of at least a part of the protein kinase catalytic domain of PDKI is a three-dimensional structure (or part thereof) determined for a polypeptide consisting of residues equivalent to residues 51 to 359 of full length human PDK1, or a fragment or fusion thereof. A method for selecting or designing a compound for modulating the activity of a hydrophobic pocket (PIF binding pocket)-containing protein kinase having a hydrophobic pocket in the position equivalent to the hydrophobic pocket of human PDKI that is defined by residues including Lys115, 20 Ile118, Ilel19, Va1124, Va1127 and/or Leu155 of full-length human PDK1 and further having a phosphate binding pocket in the position equivalent to the phosphate binding pocket of human PDKI that is defined by residues including Lys76, Arg131, Thr148 and/or Glnl50, the method comprising the step of using molecular modelling means to select or design a compound that is predicted to interact with the said hydrophobic pocket­-containing protein kinase, wherein a three-dimensional structure of a compound is compared with a three-dimensional structure of the said phosphate binding pocket and optionally also the hydrophobic pocket and/or aC helix or region interacting therewith, and a compound that is predicted to interact with the said phosphate binding pocket and optionally also the hydrophobic pocket and/or alphaC helix or region interacting therewith, is selected.