Fragment based approach
A new high speed and accurate approach of structure based drug design is offered to molecular modelers, crystallographers and medicinal chemists
Fragment based applications
MEDIT is offering a new computational drug design protocol combining local similarity of protein surfaces and a fragment-based approach [1-6]. It is based on MED-SuMo and brings together their respective advantages in an attractive way. The protocol is intended for fragment library design, lead discovery and lead optimization. Lead Discovery and Lead optimization applications are performed with MED-Hybridise.
Fragment-based drug discovery has emerged in the last decade and is in contrast to conventional high throughput screening (HTS) where fully built, “drug-sized” chemical compounds are screened for activity. Small chemical structures or fragments (100-250 Da) that intrinsically have weaker binding affinity (
Obtaining experimental structural information on fragments or ligands complexed to a target protein is a key element and also a major limitation to the number and types of target that are amenable to fragment-based drug discovery. Consequently, computational methods play a key role in deriving structural information for designing compounds that fit a particular site on a given protein.
Fig.1: The collected pool of MED-Portion chemical moities in the case of a DFG-out protein kinase query pocket. chemical moities are colored according to their subpocket.
MED-SuMo enables populating binding sites by searching and retrieving MED-portions chemical moieties from the MED-SuMo fragment database. This database of MED-Portions
, where a MED-Portion is a new structural object encoding protein-fragment binding sites, is generated with MED-Fragmentor. a collected pool of MED-Portion chemical moities is shown below in the case of a DFG-out protein kinase pocket:
Binding sites superimposition with MED-SuMo leads to ligands alignments
In our fragment-based approach protocol, we do not hybridise ligands like is was done in a pioneering work published in 2004 [7] (Figure 2.) because the retrieved ligands are found to be much more likely to have strong bumps (steric clashes) with the query protein than the smaller MED-Portion chemical moieties [1]. After a bump count between the retrieved ligands and the query protein it can be concluded that this sort of starting material is not suitable for further study, since too many bumps are present.
Fig.2: superposition of p38 MAP kinase protein structures 1DI9, 1A9U, 1BMK in the MED-SuMo interface ; potential hybridization cases: (1DI9 & 1A9U) and (1DI9 & 1BMK). The superposition of p38 MAP kinase structures (PDB codes 1DI9, 1A9U, 1BMK) leads to the superposition of their co-cristallized ligand. The ligands can be hybridised to generate new ligands [7]. MED-SuMo can automatically generate similar alignment of the protein kinases and aligned ligands can be exported in PDB or SD files for post treatments like hybridisation.
Our strategy: MED-Portion chemical moieties hopping instead of ligand hopping from one target to another
Similar protein surfaces are likely to bind the same MED-Portion chemical moiety
MED-Portion chemical moieties have smaller interaction surfaces than ligands and therefore target hopping is more likely to occur
Many interfamily hits occur: GPCR binding sites can be successfully populated [1]
References
[1] Moriaud F., Doppelt-Azeroual, O., Martin, L., Oguievetskaia, K., Koch, K., Vorotyntsev, A., Adcock, S. A., Delfaud, F. "A computational fragment-based approach at PDB scale by protein local similarity” accepted and to be published in JCIM (2009, Noordwijkerhout issue)
[2] Moriaud F., Henry T., Adcock SA, Vorotynsev AM, Martin L, Doppelt-Azeroual O., AG De Brevern and F Delfaud “A computational protocol to fragment-based drug design at PDB scale” The 8th International Conference on Chemical Structures, Noordwijkerhout, The Netherlands, 1-5 june 2008 (http://www.int-conf-chem-structures.org/pdf/C-5.pdf)
[3] Moriaud F., Henry T., Adcock SA, Vorotynsev AM, Martin L, Doppelt-Azeroual O., AG De Brevern and F Delfaud “A computational protocol to fragment-based drug design at PDB scale” The 8th International Conference on Chemical Structures, Noordwijkerhout, The Netherlands, 1-5 june 2008 (http://www.int-conf-chem-structures.org/pdf/C-5.pdf)
[4] Moriaud F., Adcock S.A., Vorotyntsev A.M., Martin L., Doppelt O., De Brevern A.G. and Delfaud F. “A computational protocol to Fragment-Based Drug Design at PDB scale”, eCheminfo InterAction Meeting, Bryn Mawr, 2007 October 15-19, Philadelphia, PA, USA (Talk http://echeminfo.com/COMTY_conf07delfaudf)
[5] Moriaud F., Adcock S.A., Vorotyntsev A.M., Martin L., Doppelt-Azeroual O., De Brevern A.G. and Delfaud F. “A computational protocol to Fragment-Based Drug Design at PDB scale”, ACS Fall 2007 prospectives Advances in Structure Based Drug Discovery, 2007 September 9-11, San Francisco, CA, USA (Poster)
[6] Moriaud F, Henry T., Adcock S.A., Vorotynsev A.M., Martin L., Doppelt-Azeroual O., De Brevern A.G., Delfaud F. “Lead optimization computational protocol at PDB scale to rationally optimize attachments to a given kinase inhibitor scaffold”, Virtual Discovey, 2008 23-24 january, Palm Springs, CA, USA (Poster)
[7] Pierce AC, Bemis GW, “BREED: generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease” J. Med. Chem. (2004) May 20;47(11):2768-75
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