Homology Modeling of the Catalytic Domains of Gelatinases and Docking Study with Their Inhibitors

Three-dimensional models of the gelatinase catalytic domains were built from collagenase structures by the homology modeling technique. The docking of different types of inhibitors was then studied in an attempt to obtain structural insight into their binding modes. In the case of an amide compound docked with gelatinase A, almost the same binding mode was obtained as that observed in the crystal structure of another amide compound complexed with collagenase. With respect to our series of matlystatin analogs, the key hydrogen bonding and hydrophobic interactions with gelatinase B were similar to those of the above amide compounds, although these derivatives have a unique piperazine ring. The length and hydrophobic nature of the S1' subsite was well consistent with the observation that the inhibitory activity rises as the alkyl chain at P1' becomes longer. The binding mode of a sulfonamide inhibitor was slightly different from that of amide and piperazine inhibitors, but similar to that proposed recently for another sulfonamide inhibitor.