DOCKING OF A SERIES OF PEPTIDE-BASED INTERLEUKIN-1-BETA CONVERTING-ENZYME INHIBITORS WITH ASPARTYL HEMIACETALS, ALPHA((2,6-DICHLOROBENZOYL)OXY)METHYL AND (ACYLOXY)METHYL KETONE MOIETIES

The enzyme-binding mode of a series of interleukin-1 beta converting e nzyme (ICE) inhibitors has been analysed on the basis of the crystal s tructure of the complex between hICE and tetrapeptide aldehyde. The co nformation of these ligands were explored by performing molecular dyna mics simulations at 100 ps. The conformation adopted by these inhibito rs was very similar to and could be superimposable onto the regions of crystal structure. The active and the low energy conformers were dock ed either by grid or manually into the binding site. The analysis of t he resulting model indicated that O-benzylacyl group of aspartyl hemia cetals interact with Cys285 and the large substituents: semicarbazone, 2,6-bis(trifluoromethyl) benzoate, other leaving groups of (acyloxy)m ethyl and alpha-((2,6-dichlorobenzoyl)oxy)methyl ketone series of P1 s ite protrude from the surface of Cys285 and interact with Val338, whic h is located below the binding pocket. The hydrogen bonding interactio n between -NH of semicarbazone and Cys285 seems to have significant ro le. The total potential energy including intermolecular interaction en ergy, consisting of van der Waals and electrostatic energies were calc ulated. The resulting model is qualitatively consistent with the repor ted experimental data and can be useful for the design of more potent inhibitors of ICE.