期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 52, 期 1, 页码 210-224出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci2004779
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资金
- Le Ministere du Developpement Economique, de l'Innovation et de l'Exportation du Quebec
- AstraZeneca RD Montreal
- NSERC
- CIHR
- CIHR (Strategic Training Initiative in Chemical Biology)
- McGill University
- DDTP-CIHR
- CIHR (Strategic Training Initiative in Drug Discovery and Development)
- CONACyT (Consejo Nacional de Ciencia y Tecnologia)
As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e., virtual, theoretical) and medicinal (i.e., experimental, intuitive) chemistry to take advantage of the full potential of both. For this purpose, we have developed a Web-based platform, FORECASTER, and a number of programs (e.g., PREPARE, REACT, SELECT) with the aim of combining computational chemistry and medicinal chemistry expertise to facilitate drug discovery and development and more specifically to integrate synthesis into computer-aided drug design. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries, filter and extract a highly diverse library from the NCI database, and dock them to the estrogen receptor (ER), with all of these steps being fully automated by computational chemists for use by medicinal chemists. As a result, virtual screening of a diverse library seeded with active compounds followed by a search for analogs yielded an enrichment factor of 129, with 98% of the seeded active compounds recovered, while the screening of a designed virtual combinatorial library including known actives yielded an area under the receiver operating characteristic (AU-ROC) of 0.78. The lead optimization proved less successful, further demonstrating the challenge to simulate structure activity relationship studies.
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