METHODS OF DESIGNING SPECIFIC AFFECTORS USING THREE-DIMENSIONAL CONFORMATION OF ENZYME/AFFECTOR COMPLEX

摘要

The present invention includes methods for rational drug design. One exemplary method disclosed herein teaches the preparation of a highly specific affector of a first enzyme when the first enzyme is a member of a class of enzymes having a conserved catalytic core with a plurality of invariant residues. This method comprises identifying a second enzyme that is a member of that class of enzymes and has a known affector. The affector can be an inhibitor or activator of the second enzyme. In the practise of the method, a first complex is formed between the second enzyme and the known affector and data is obtained regarding the three-dimensional coordinates of the invariant residues in the complex. These coordinates are used to form a template. A model is then generated in which the first enzyme is in a conformation with the invariant residues in substantially the same conformation as in the template. Changes in the variable residues of the catalytic core of the first enzyme are compared to the variable residues in the catalytic core of the second enzyme. The second enzyme is modified to include these non-conserved changes and an affector is designed using computer modelling that will induce a conformation on the catalytic core of the first enzyme in which the invariant residues are in substantially the same coordinates as the coordinates of the template when the first enzyme is formed as a second complex with the newly designed affector. The designed affector can be further refined to provide improved affector activity.