The Conformation Search Problem

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1 Jon Sutter Senior Manager Life Sciences R&D Jiabo Li Senior Scientist Life Sciences R&D CAESAR: Conformer Algorithm based on Energy Screening and Recursive Buildup The Conformation Search Problem 3D conformation generation is important in many applications 3D pharmacophore generation Database building and searching Docking etc. Efficient search is a challenge Exponential explosion of conformer space Ring flexibility Removing duplicate conformations while considering topological symmetry 1

2 Timeline of CAESAR Early Validation Validation Initial Idea Sabbatical Discovery Studio 1.7 work begins. D.S. 1.7 Released Now The CAESAR Algorithm 1. Recursively partition 2. Ring Conformations 3. Recursively assemble E AB = E A + E B + E A B 4. Remove symmetry duplicates 5. Quickly filter out bad clashes 2

3 Split Molecule and Generate Ring Conformers Each tree node is either a ring or a rigid structure A molecule tree is recursively partitioned into the smallest units At top level, a tree is divided into two sub-trees of approximately equal complexity Repeat steps for the two sub-trees until no partitioning can be performed Compute ring conformations Recursive Conformer Assembling Confs (FragA) Confs (FragB) Assemble confs for FragAB Step 1. Select ConfA, ConfB and rotation from a pool of N A xn B xn R combinations Step 2. Fast energy filtering Step 3. Repeat Step 1 and 2 until enough conformations are generated for FragAB Step 4: Repeat 1-3 for upper level 3

4 Energy Screening Confs (FragA) Confs (FragB) Fast energy computation and filtering as follows: Assemble confs for FragAB E(ConfAB) = E (ConfA) + E (ConfB) + E (ConfA-ConfB) Removing Duplicate Conformations Normally quick, but if considering topological symmetry can be costly to enumerate all possibilities. There is a potentially significant time savings if we can avoid creating the duplicates in the first place. Since we are assembling the molecules from pieces, we can do this in an intelligent manner to avoid creating duplicate conformers. 4

5 Symmetry Unique Rotations A B The most common cases are 2- fold symmetry such as phenyl groups and 3-fold symmetry such as t-butyl groups. If the default number of torsion grids is set to 6, then only one torsion angle is symmetry unique for this case CAESAR flow diagram Split molecule and generate ring conformations Join each pair of fragments Select a combination of Conformer A, Conformer B and a Symmetry Unique Torsion angle Energy Filtering No Enough? Yes No Top? Yes Done 5

6 Performance and Validation Questions How well does it sample conformational space? Are database search results similar? Is CAESAR able to find conformations close to the bioactive conformer? How fast is CAESAR? 6

7 Datasets 919 ligands extracted from PDB* 168 Molecules from Derwent Drug World Index 10 Sulfonamide Molecules ~50,000 Molecule Database (Maybridge) Molecular Weight (x100) * Thanks to Dr. Johannes Kirchmair and Professor Thierry Langer of the University of Innsbruck Number of Rotatable Bonds Similarity of Database Search Results Query Number of Hits* FAST CAESAR Number of Common Hits Similarity (%) Pharm_3F Pharm_5F Shape Pharm_5F + Shape Total hits * Two Maybridge databases were built with FAST and CAESAR. The default settings were used. 7

8 Bioactive Conformations? Extract protein-ligand complexes from the Protein Data Bank (PDB) Generate conformations without knowledge of crystal structure conformation Compare conformations to crystal structure Kirchmair, J., et al. J. Chem. Inf. Model. 45(2): (2005). Protocol 8

9 Bioactive conformations PDB Data Average RMS RMS < 0.5 RMS < 1.0 RMS < 2.0 RMS < 3.0 CAESAR % 49% 92% 99% FAST % 50% 93% 99% Speed Test: CAESAR vs. Catalyst FAST Data Set WDI168 (168 molecules) Sulfonamide10 10 sulfonamides PDB ligands from PDB MaxConfs Speed-up (x faster) Note: Pre-built ring fragment database file is used. 9

10 Conclusions CAESAR provides conformational coverage similar to Catalyst FAST conformer generation CAESAR is 5-20 times faster than FAST Thanks C.M. Venkatachalam (Venkat) Remy Hoffman Marvin Waldman Paul Flook Samuel Toba Xuan Hong Shihka Varma Tedman Ehlers Johannes Kirchmair, University of Innsbruck Thierry Langer, Univeristy of Innsbruck 10

11 Questions: Jon Sutter Ph.D. Jiabo Li Ph.D. 11