CONSTRAINED SEARCH OF CONFORMATIONAL HYPERSPACE OF INACTIVATORS OF GLUCOSAMINE-6-PHOSPHATE SYNTHASE

Glucosamine-6-phosphate (GlcN-6-P) synthase (EC 2.6.1.16) is a key enz yme in amino sugar metabolism in micro-organisms and its selective and irreversible inhibitors can become valuable antifungal drugs. We perf ormed a constrained search of the conformational hyperspace of glutami ne and of the set of specific inactivators of the enzyme, as well as o f some non-specific inhibitors of many cysteine containing enzymes. Fr om these calculations we obtained spatial relationships of functional groups, the presence and specific orientation of which in the active s ite of the enzyme is important for effective and selective action of t he inhibitor. Subsequent quantum chemical calculations confirmed the c orrectness of the pharmacophora conformation we obtained. Pharmacophor e conformation of FMDP molecule, the most potent inhibitor in the sele ctive inhibitors group, is placed close to the energy minimum on the c onformational energy map.