ライフサイエンスセミナーのご案内
バイオインフォマティクスセンター・スーパーコンピュータシステム・
薬学研究科（博士後期課程特論講座）による合同のライフサイエンスセミナーを
以下の通り開催いたします。
| 名称 | ライフサイエンスセミナー |
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| 日時 | 2012年10月25日（木) 15:00 - 16:30 |
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| 場所 | 化学研究所 総合研究実験棟2階 CB207(化研へのアクセス) |
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| 講師 | Didier ROGNAN氏(フランス国立科学研究センター 研究ディレクター) |
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| 対象 | 京都大学に属する教職員/学生/研究員など |
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| 申込 | 本セミナーは申込は不要です。当日直接会場にお越しください。 |
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| 当日必要なもの |
特にありません。
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| 内容 |
[Title]
Fingerprinting protein cavities and protein-ligand complexes for drug design
[Abstract]
The combinatorial explosion of bioactivity and structural data on
protein-ligand complexes of pharmaceutical interest enable the generation of
large matrices to better understand reasons for either fine
selectivity or polypharmacology.
We herewith present various 1-D fingerprints featuring either
druggable cavity attributes or protein-ligand complexes in various drug design scenarios:
-predict the structural druggability of any given pocket
-predict possible off-targets from binding site similarity calculations
-screen a ligand against 3600 targets to get a polypharmacology profile
-post-process docking poses by interaction fingerprint similarity
-compare interaction patterns across the Protein Data Bank to enable scaffold hopping
当日時間に余裕がある場合には、以下のタイトルの講演もされる予定です。
[Title]
Receptor-Ligand Pharmacophores: A novel structure-based screening weapon
for ligand profiling and discovery of protein-protein interface inhibitors
[Abstract]
We herewith present PharmaDB, a collection of 68,000 pharmacophores derived from 8,000 high resolution protein-ligand complexes from the sc-PDB dataset. A maximum of 10 pharmacophores (3-6 features) per complex are automatically derived from the simple inspection of receptor-ligand atomic coordinates, and further ranked by expected decreasing selectivity using a genetic function approximation.
In a first application, receptor-ligand pharmacophore search was compared to ligand-centric (2-D and 3-D similarity searches) and docking methods in profiling a set of 157 diverse ligands against a panel of 2,556 unique targets of known X-ray structure. As expected, ligand-based methods outperformed, in most of the cases, structure-based approaches in ranking the true targets among the top 1% scoring entries. However, we could identify ligands for which only a single method was successful. Receptor-ligand-based pharmacophore search is notably a very fast and reliable alternative to docking in which constraints are explicitly defined, and which generates high-quality poses.
In a second scenario, the method was applied (in parallel to docking) to screen a collection of 3 million commercially-available compounds for finding the very first inhibitors of two independent protein-protein interfaces (PPI). Strikingly, only protein-protein pharmacophore mapping was able to identify micromolar hits which were later confirmed by binding and functional assays. Although more prospective examples are required to derive general rules, protein-protein pharmacophore search appears a very promising and robust tool to find PPI inhibitors.
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