IDP_Problem Statement - Shaastra

BioDocks!, Shaastra 2011, IIT Madras
Problem statement from VLife Sciences Technologies Pvt Ltd.,Pune, India
Background:
Computer aided drug design approaches in general and target structure based
approaches in particular, play key roles in the entire domain of drug design and
discovery. Among structure based approaches, molecular docking of potential lead
molecules to corresponding protein targets is undeniably one of the most important
methods utilized today world-wide.
In that light and in keeping with the theme of BioDocks!, Shaastra 2011, IIT Madras,
we propose the following industrially relevant research problem to all contestants. In
spite of having a rich plethora of docking methods and tools available (both
commercial and public) today, none of them singularly can address pose prediction
closest to the crystal pose of the native ligand generically across diverse targets. The
two key aspects here are the pose generation methods and the corresponding
docking scoring functions.
The problem
In light of that, our present short research project/problem to all contestants is to try
to arrive at a generic methodology to address the broad problem area mentioned
above. The exact steps to be followed are detailed below:
1. We are providing names of a set of 7 co-crystallized protein-native ligand
complexes (cf. Appendix 1) whose structures can be easily downloaded from the pdb
site (http://www.pdb.org) and used for docking. These 7 co-crystallized protein-ligand
complexes are chosen from different protein families corresponding to key
therapeutic areas like diabetes, cancer, inflammation and several others of industrial
and social relevance. We are providing the chain details of the target and the
corresponding co-crystallized ligand names (cf. Appendix 1) as well as the 2D input
sdf files for the co-crystallized ligands to be used for docking.

2. As a broad outline, the contestants are suggested to extract each of the cocrystallized
native ligand out of the corresponding complex and use them as
reference native ligand for alignment with the docked pose later on. It should also be
kept in mind by contestants that appropriate conformers of the co-crystallized ligand
for each target should be used for docking.
3. The conformers are to be docked back to the respective target protein (apo
structure without the ligand) and the best docked pose of the ligand closest to the
original crystal ligand pose has to be found out. This is expected be quantified in
terms of RMSD of alignment of the docked pose with the native crystal pose.
4. The best pose for each such ligand for all the 7 targets are to be recorded by
contestants.
5. The contestants are expected to come up with a methodology/strategy that
generically applies across all 7 targets in terms of best pose (criteria for "best" as
described in point 3 above) capturing. It should be noted that the methodology
should not be biased by any existing binding pose information for finalizing the best
pose. The details of this methodology with its working steps should be reported as
part of the results of the work carried out. This same method has to be applied to a
blind docking test before the judges in the final evaluation phase of the contest.
6. The results of RMSD of alignment of docked pose with native crystal pose for
each ligand across all 7 targets using the same methodology/strategy should be
reported as a Table containing names of each of the ligand, their corresponding
target with the chain used and the RMSD results.
7. The maximum working time allowed for carrying out this work along with the
results report is 15 days.
8. Short-listing of candidates will be done based on their results (as detailed in points
5, 6). The results should contain both the method/strategy developed with any known
docking tool(s) as well as the RMSDs of alignment of docked pose with native crystal
pose for each ligand across all 7 targets.
9. The short-listed candidates are expected to carry out the following at the contest
venue based on which they will be judged for winning positions:

i) Demonstrate the reported RMSD results for any one target (chosen by the judges)
out of the given 7 targets by actually carrying out the docking using their developed
strategy.
ii) Apply their method/strategy to 1-2 protein targets(different from the 7 originally
given) which will be a blind test set provided by VLife Sciences Technologies to all
short-listed contestants on the contest judging day. The results of RMSD of
alignment of docked pose with native crystal pose for each of these 1-2 test set
ligands are to be reported to the judges.
APPENDIX
Serial No. Target PDB ID Co-crystallized
Ligand Name
Chain of Target to
be used
1 1NNY 515 A
2 1O6K ANP A
3 1POE GEL A
4 1Z95 198 A
5 3I6C GIA B
6 3IJJ AVR C
7 3KS9 Z99 A