Thermolysin inhibitors molecular modeling

Wasserman and Hodge (290) used molecular dynamics to dock thermolysin inhibitors to an approximate model of the enzyme, with flexibility in the active site (3 8 of 314 residues) and ligand and with the rest of the enzyme represented by a grid approximation. A solvation model was used to compensate for desolvation in complex formation. To get 22 of 25 runs to orient the hydroxamate function correctly, the hydroxamate oxygens of the starting conformation were initialized within 4 A of the zinc. If they were allowed to vary to 8 A, then only 3 of 24 runs placed the ligand correctly. Obviously, there is a serious sampling problem. 

Waller, C.L. and Marshall, G.R. (1993). Three Dimensional Quantitative Structure-Activity Relationship of Angiotesin Converting Enzyme and Thermolysin Inhibitors. 2. A Comparison of CoMFA Models Incorporating Molecular Orbital Fields and Desolvation Free Energies Based on Active Analog and Complementary Receptor Field Alignment Rules. JMeeLChem., 36,2390-2403. 

Waller CL, Marshall GR (1993) Three-dimensional quantitative structure-activity relationship of angiotesin-converting enzyme and thermolysin inhibitors. II. A comparison of CoMFA models incorporating molecular orbital fields and desolvation free energies based on active-analog and complementary-receptor-field alignment rules. J Med Chem 36(16) 2390-2403... 

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