QuantumBio will be co-sponsoring the Perspectives in Applied Computational Methods session at the 2012 American Chemical Society meeting in Philadelphia, PA August 21-22. The following two abstracts will be presented:

293 – Data-driven docking: When dock’n it old school just doesn’t cut it!

Lance M Westerhoff, lance@quantumbioinc.com, Oleg Borbulevych, Joshua A Plumley. QuantumBio Inc, State College, PA 16801, United States

Of crucial importance to structure based drug discovery (SBDD) and fragment based drug discovery (FBDD) is the accurate prediction and scoring of binding modes of novel ligands and especially fragments within the pocket of a known receptor. Using a combination of shape-driven docking; the MOE/DivCon, linear scaling, semiempirical quantum mechanics (SE-QM) interaction profiling platform; and the PHENIX/DivCon X-ray refinement package, the present study explores how well binding modes can be predicted, refined, and finally characterized. This process yields a handful of high quality binding modes for each ligand or fragment, and once these species are placed, each model is refined to address any clashes using the PHENIX/DivCon X-ray refinement package. In addition to discussing the applicability of this novel method to SBDD and FBDD, the SE-QM interaction energies (e.g. QMScore and QM-PWD) along with changes in ligand strain observed upon refinement will also be reported.

Tuesday, August 21, 2012 03:45 PM
Perspectives in Applied Computational Methods (01:30 PM – 04:30 PM)
Location: Pennsylvania Convention Center
Room: 118 B

478 – Systematic study of the ligand strain energy derived from the quantum mechanics crystallographic refinement using the linear scaling program DivCon integrated into the PHENIX package

Oleg Y Borbulevych, oleg@quantumbioinc.com, Joshua A Plumley, Lance M Westerhoff. Research & Development, QuantumBio Inc, State College, PA 16801, United States

The strain energy – defined as the difference between the energy of the isolated ligand and the protein bound ligand structure – serves as an important quality indicator of the protein-ligand structures. However, the crystal structures deposited to PDB often exhibit unreasonable ligand strain energies due to problematic ligand geometry as a consequence of using conventional refinement methods. Recently we replaced the stereochemistry restraints used in conventional refinement with semi-empirical quantum mechanics (SE-QM) gradients generated in real-time over the course of the refinement to achieve improved protein-ligand structure.

We conducted a systematic characterization of the strain energy for population of pharmaceutically relevant protein-ligand structures downloaded from PDB. Those structures with resolutions ranging from 1.5 to 3Ã… and with the highest deposited ligand-structure strain energy were re-refined and scored using our PHENIX/DivCon methodology. Observed improvements in ligand strain will be reported along with the results pertaining to changes in predicted SE-QM interaction energies

Wednesday, August 22, 2012 10:55 AM
Perspectives in Applied Computational Methods (09:00 AM – 11:40 AM)
Location: Pennsylvania Convention Center
Room: 118 B