Molecules derived from mechanism based drug design

4 A molecule of claim 1 wherein said molecule comprises the minimum quantity of atoms to trigger the reaction of metallo protease and has the following basic structure:

• 105
• wherein B can be any basic group;
• R1 and R2 can be any functional group;
• and
• x can be any atom or group that is more electronegative than sp2 carbon.

A system for developing a small molecule wherein said system comprises:

• (a) a method to compare the stabilization energies of a given reaction between a catalytic residue of an enzyme to residues of a substrate to determine the trigger mechanism for the given reaction,
• (b) a minimal amount of atoms comprising said trigger mechanism of the given reaction;
• and
• (c) a ligand wherein said minimal amount of atoms are positioned on said ligand to form said molecule.

A method for determining the trigger mechanism of a given reaction wherein said method uses a matrix involving the steps of:

• (a) performing ab initio calculations on a class of enzymes to compare a reactive residue associated with a catalytic site common to the class of enzymes to a reactive residue with one or more substrates associated with the class of enzymes;
• (b) using the information generated from step (a) and performing further ab initio calculations on a subclass of enzymes by comparing further reactive residues associated with the catalytic site common to the subclass of enzymes with one or more substates associated with the subclass of enzymes;
• (c) using the information generated from step (b) and performing further ab initio calculations on a single enzyme from the subclass of enzymes by comparing all reaction residues associated with the catalytic site of the enzyme with one or more substrates associated with the enzyme;
• and
• (d) using the information generated from step (c) to determine the trigger mechanism for the enzyme.

A method for determining a trigger mechanism for a given reaction comprising the steps of:

• (a) performing ab initio calculations to determine the stability of each potential interaction between each active site residue of an enzyme and a chemical moiety of one or more substrates of said enzyme;
• (b) analyzing the calculated stabilization energies, wherein the most negative energies are the most reactive species and the most positive energies are the least reactive species;
• and
• (c) combining the chemical moieties that were calculated to be the most reactive, or the least reactive, with each corresponding catalytic residue on a compound scaffold.

A method for deteriming the trigger mechanism of a given reaction comprising the steps of

• (a) aligning a protein sequence of an enzyme with other proteins and determining by homology the general class of the enzyme;
• (b) performing biochemical assays to determine the reaction performed by the enzyme,
• (c) performing site-directed mutagenesis of conserved amino acids and determining if the mutated residues act in the reaction mechanism;
• (d) determining the mechanism of catalytic action for the enzyme;
• and
• (e) performing ab initio calculations to determine the stability of each potential interaction between each active site residue of the enzyme and a chemical moiety of one or more substrates of said enzyme.

A method of designing a small molecule that interacts with the active site of a certain enzyme comprising the steps of.

• (a) aligning the protein sequence of the enzyme with other proteins and determining by homology the general class of enzyme;
• (b) performing biochemical assays to determine the reaction performed by the enzyme;
• (c) performing site-directed mutagenesis of conserved amino acids and determining if the mutated residues act in the reaction mechanism;
• (d) determining the mechanism of catalytic action for the enzyme;
• (e) performing ab initio calculations to determine the stability of each potential interaction between each active site residue of the enzyme and a chemical moiety of one or more substrates of said enzyme;
• (f) analyzing the calculated stabilization energies, wherein the most negative energies are the most reactive species and the most positive energies are the least reactive species;
• and
• (g) combining the chemical moieties that were calculated to be the most reactive, or the least reactive, with each corresponding catalytic residue on a compound scaffold.