The genesis of the meeting was the sense on the part of computational chemists in the pharmaceutical industry that the field of structure-based ligand discovery had reached a plateau. That is, excellent chemical intuition from the scientist behind the computer screen remains essential for the application of the methods of structure-based drug design. Recent publications comparing the capabilities of numerous docking and scoring algorithms support this position. The key question, then, is what should funding agencies do to push the field to the next level. A related question is what can the users in industry do to facilitate this next step.
The meeting began by examining the premise that the major challenge in structure-based drug design is scoring, not docking. The accuracy of predicting the correct pose of an active compound can be quite good. Virtual screening of a library leading to enrichment can be done reasonably well, although there is no
a priori way to know which docking algorithm will work best on the target of interest. The real goal is not only to rank order ligands by binding but to predict actual affinities well enough that the number of compounds that need be evaluated experimentally can be significantly reduced.
Since one is always sacrificing accuracy for computational speed, especially in screening large libraries, we might anticipate that faster computers solve the problem by allowing us to routinely use more accurate computational methods. The consensus of the group, however, was that unless we can get the other things right, faster computers will only get us part way. In fact, given the inherent problems with structure-based drug design, it is remarkable that it works as well as it does.
So why are we not making more rapid progress? It is clear that we are not getting the physical chemistry right. Two examples:
To improve this situation, there are a number of problems that must be solved. It is hard to deal with water molecules—that is, to determine which are intimately involved in the binding of the ligand to the target. Dealing with other basic physical chemical properties, such as pKa, salt effects, and conformational states is also difficult. Entropies and enthalpies are notoriously hard to calculate. There is also the problem of accounting for protein reorganization as a result of ligand docking, as in the case of HIV reverse transcriptase.
Thus in looking to the future, one has to consider improvements in both empirical and physics-based models. What are the known gaps in our understanding of the physics of the process? Could there be as yet unanticipated gaps? Would better sampling help? Can searches be done more efficiently? How much can we gain from clever engineering and optimization? And how far will incremental improvements take us? Do we need fundamental new discoveries?
One issue that can be addressed is how to evaluate our methods, to know if they are improving. One mechanism to explore the state of ligand docking could be a contest similar in nature to the "protein folding contest" or CASP. The idea of a ligand-docking contest did not receive overwhelming support at this time, as the need for providing additional systematic data was considered more pressing. The group elected to defer discussion of contests to a later date, but did not rule out the concept.
Clearly good datasets containing measured affinities of ligands for targets are necessary. Some datasets, such as those for HIV protease are already available. However, more sets which represent a range of protein structures are needed; agreement on common benchmarks in the field would also be desirable. For a given target, ligands with a wide range of affinities, including positives and negatives ("decoys") are also needed. Much of this data resides in industry. The release of those data for which adequate intellectual property protection has been obtained or which represent "abandoned" projects would be extremely valuable for this whole field. Corollary datasets such as crystal structures generated for a series of bound ligands are also important. Again many of these valuable data sets reside in industry. There are obstacles for the release of these data. One is the lack of incentives. The second is cost. For example, crystal structures may need to be further refined or formatted for submission to the Protein Data Bank, PDB.
The generation of other "standard" data, for example solubility, for a well-defined set of compounds is also important to "train" the algorithms. Given its mission, the National Institute of Standards and Technology (NIST) might prove to be a valuable player. Finally, there also needs to be the capability to create some "living" data systems, for which new compounds, structures and experimental data can be generated when needed to more rigorously test improved docking and screening methods.
If data are released, how can they be made available to the scientific community? Chris Austin presented the PubChem website http://pubchem.ncbi.nlm.nih.gov/ which is collecting and making available the kinds of data envisaged here. This database would seem to be an ideal repository for these data. Discussions should continue.
Attendees agreed that an important step in facilitating the improvement of structure-based drug design methods is to make additional data available to researchers. Since release of such data from the pharmaceutical industry requires that we design a process that holds substantial promise , it was agreed to hold another meeting in fairly short order, in three months. Included, in addition to scientists from industry and academia, should be representatives from the Foundation for the NIH, the NIH molecular libraries roadmap, and the PubChem database. There was some sympathy for holding the meeting at Asilomar. Drs. Peishoff and Shoichet agreed to chair the meeting.
Christopher P. Austin, M.D.Senior Advisor to the Director for Translational Research
Director, NIH Chemical Genomics CenterNational Human Genome Research InstituteNational Institutes of HealthBuilding 31, Room 4B0931 Center DriveBethesda, MD 20892Tel: 301-594-6238Fax: 301-402-0837
Jeremy M. Berg, Ph.D.DirectorNational Institute of General Medical SciencesNational Institute of Health45 Center Drive MSC 6200Bethesda, MD 20892-6200Tel: 301-594-2172Fax: 301-402-0156
Jeff Blaney, Ph.D.Vice president, Lead Discovery
Structural Genomix10505 Roselle StreetSan Diego, CA 92121Tel: 858-228-1495Fax: 858-558-0642
James Cassatt, Ph.D.DirectorCell Biology & Biophysics DivisionNational Institute of General Medical SciencesNational Institutes of Health45 Center Drive MSC 6200Bethesda, MD 20892-6200Tel: 301-594-0828Fax: 301-480-2004
Wendy CornellDirectorMolecular SystemsBasic ChemistryMerck Research Laboratories126 East Lincoln AvenueRahway, NJ 07065Tel: 732-594-4954
Ernesto Freire, Ph.D.Henry Walters ProfessorBiology and BiophysicsJohns Hopkins University3400 N. Charles Street114 Mudd HallBaltimore, MD 21218Tel: 410-516-7743Fax: 410-516-6469
Michael K. Gilson, M.D., Ph.D.Professor and CARB FellowCenter for Advanced Research in BiotechnologyUniversity of Maryland and Biotechnology Institute9600 Gudeisky DriveTel: 240-314-6217Fax: 240-314-6255
Barry Honig, Ph.D.Principal InvestigatorDepartment of BiochemistryColumbia UniversityBox 36, BB2-221630 West 168th StreetNew York, NY 10032Tel: 212-305-8283Fax: 212-305-6926
William L. Jorgensen, Ph.D.Department of ChemistryYale UniversityNew Haven, CT 06520-8107Tel: 203-432-6278Fax: 203-432-6299
Leslie A. Kuhn, Ph.D.Professor, Biochemistry & Molecular Biology, Computer Sciences & Engineering, and Physics & AstronomyCo-Director, Quantitative Biology & Modeling InitiativeMichigan State University502C Biochemistry BuildingEast Lansing, MI 48824-1319Tel: 517-353-8745Fax: 517-353-9334
Deborah A. LoughneyDirector, Computer-Assisted Drug DesignBristol-Myers Squibb CompanyP.O. Box 4000Princeton, N.J. 08543-4000Tel: 609-252-6054Fax: 609-252-6012
Barbara Mittleman, M.D.Chief, Scientific Interchange Section
Office of Science TechnologyNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthBuilding 10, Room 9N118ABethesda, MD 20892Tel: 301-402-7696Fax: 301-402-0765
Manuel A. Navia, Ph.D.Drug Development Strategic AdvisorOxford Biosciences Partners222 Berkley Street, Suite 1650Boston, MA 02116Tel: 617-357-7474Fax: 781-389-0686
Arthur J. Olson, Ph.D.ProfessorDepartment of Molecular BiologyThe Scripps Research InstituteLa Jolla, CA 92037Tel: 858-784-9702Fax: 858-784-2860
Catherine E. Peishoff, Ph.D.Site Director, Computational Analytical & Structural SciencesGlaxoSmithKline1250 S. Collegeville RoadUP12-210, PO Box 5089Collegeville, PA 19426Tel: 610-917-6585Fax: 610-917-7393
Brian Shoichet, Ph.D.ProfessorDepartment of Pharmaceutical ChemistryUniversity of California San Francisco1700 4th Street, QB3 BuildingRoom 508DSan Francisco, CA 94143-2550Tel: 415- 514-4126Fax: 415- 502-1411
Janna P. Wehrle, Ph.D.Program DirectorCell Biology & Biophysics DivisionNational Institute of General Medical SciencesNational Institutes of Health45 Center Drive MSC 6200Bethesda, MD 20892-6200Tel: 301-594-5950Fax: 301-480-2004
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