Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity

International audienceBACKGROUND: Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community. RESULTS: We introduce a new approach (LigCSRre) to the 3D ligand similarity search of drug candidates. It combines a 3D maximum common substructure search algorithm independent on atom order with a tunable description of atomic compatibilities to prune the search and increase its physico-chemical relevance. We show, on 47 experimentally validated active compounds across five protein targets having different specificities, that for single compound search, the approach is able to recover on average 52% of the co-actives in the top 1% of the ranked list which is better than gold standards of the field. Moreover, the combination of several runs on a single protein target using different query active compounds shows a remarkable improvement in enrichment. Such Results demonstrate LigCSRre as a valuable tool for ligand-based screening. CONCLUSION: LigCSRre constitutes a new efficient and generic approach to the 3D similarity screening of small compounds, whose flexible design opens the door to many enhancements. The program is freely available to the academics for non-profit research at: http://bioserv.rpbs.univ-paris-diderot.fr/LigCSRre.html

A topology-based investigation of protein interaction sites using Hydrophobic Cluster Analysis

International audienc

Determination of French influenza outbreaks periods between 1985 and 2011 through a web-based Delphi method.

International audienceBACKGROUND: Assessing the accuracy of influenza epidemic periods determined by statistical models is important to improve the performance of algorithms used in real-time syndromic surveillance systems. This is a difficult problem to address in the absence of a reliable gold standard. The objective of this study is to establish an expert-based determination of the start and the end of influenza epidemics in France. METHODS: A three-round international web-based Delphi survey was proposed to 288 eligible influenza experts. Fifty-seven (20%) experts completed the three-rounds of the study. The experts were invited to indicate the starting and the ending week of influenza epidemics, on 32 time-series graphs of influenza seasons drawn using data from the French Sentinelles Network (Influenza-like illness incidence rates) and virological data from the WHO-FluNet. Twenty-six of 32 time-series graphs proposed corresponded to each of the French influenza seasons observed between 1985 and 2011. Six influenza seasons were proposed twice at each round to measure variation among expert responses. RESULTS: We obtained consensual results for 88% (23/26) of the epidemic periods. In two or three rounds (depending on the season) answers gathered around modes, and the internal control demonstrated a good reproducibility of the answers. Virological data did not appear to have a significant impact on the answers or the level of consensus, except for a season with a major mismatch between virological and incidence data timings. CONCLUSIONS: Thanks to this international web-based Delphi survey, we obtained reproducible, stable and consensual results for the majority of the French influenza epidemic curves analysed. The detailed curves together with the estimates from the Delphi study could be a helpful tool for assessing the performance of statistical outbreak detection methods, in order to optimize them