These results indicate that it is possible to obtain computer docked structures that are virtually identical to experiment when the binding conformation is known. We are currently working on flexible docking procedures while trying to maintain the goal of a rapid screen. Programs such as DOCK 4.0 will not perform flexible docking on the ten molecules used in our study since they do not have proper anchor points and have more than eight rotatable bands. The current algorithms we employ dock each rigid structure in approximately 2.5 seconds when run on a DEC-alpha 440MHz processor. With further algorithmic development and increases in processor speed we hope to be able to perform several dockings per second.
Increased speed is necessary to realistically accomplish flexible docking of drug-like molecules.
This need for speed is even more evident in the next example where we screen the NCI database for compounds that fit the HIV-1 RT NNI binding site. We started from the nevirapine bound HIV-1 RT crystal structure and first determined whether our program would correctly dock the inhibitor back into the protein. The results of our docking procedure are shown Figured F-2. Based on the success of the nevirapine results, we performed a screen of the NCI 3D database in the same binding cavity as nevirapine. This took almost eight seconds per compound with the program running on an IBM SP-2 containing 66MHz Power2 chips.