Autodock..ing

My very first experience with automated docking came about four years ago when my boss decided to find out whether docking algorithms could be helpful in our search for drugs that bound to the pentraxin proteins serum amyloid P component (SAP) and C-reactive protein (CRP). As we had a number of crystal structures, and I had spent the first year of my PhD experimentally measuring Kd's, enthalpy and entropy of binding using Isothermal titration calorimetry, my boss figured it would make a nice chapter in my thesis if I evaluated automated docking. I chose to use AUTODOCK (then ver.2.4) because it was free and the developers seemed quite keen to help.

I have posted a snippet of my methods and results from the chapter of my thesis relating to this work here. Essentially I found that AUTODOCK was unable to deal with calcium atoms. After a bit of to-ing and fro-ing with the developers I was able to come up with some parameters that seemed to allow the ligands to dock in a semi-satisfactory manner, and although the actual orientations seemed correct (and the program was mostly able to order the ligands in order of affinity) the calculated delta-G's bared little resemblance to the experimentally measured parameters. There was also evidence that the electrostatics of the interaction completely dominated the calculations whilst the critically important hydrophobic interactions and hydrogen bonding were less important for the docking.

In retrospect i should have written up and published these results at the time, however the experiments were done prior to some big publications and we did not want to risk the chances of our Nature papers!