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Principal Investigator: MARC NICKLAUS
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2024
Award: $158,959
Funding agency: National Cancer Institute
In collaboration with several Principal Investigators at the CCR/NCI and NIH, in silico screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the CADD Group's resources, including our screening databases to generate lists of compounds to be purchased from commercial suppliers, with the goal of obtaining novel lead compounds in in vitro and/or cell-based assays. We have been working on the interaction of the transcription factor HIF-1 alpha with cofactor p300, in collaboration with William Douglas Figg Sr., GMB, CCR, NCI and Nigel Greig from IRP, NIA, NIH. A very important part of our in silico screening collaboration has been with Nadya Tarasova, CIL, CCR, NCI. In the context of our SAVI project (see Project 2), we have applied the SAVI Database to find active molecules against cancer, SARS-Cov-2 targets, and, to some extent, HIV-1, targets. Our work on STAT3 N-terminal domain (ND), a promising target since it has been shown that a STAT3 ND lipopeptide inhibitor induces cell death through activation of proapoptotic genes in tumor cells but not normal epithelial cells has yielded small molecule leads in the screening that are more potent than lipopeptide STAT3 ND inhibitors. The compounds suppress STAT3 signaling and are selectively toxic to tumor cells. We have recently analyzed the correlation of protein binding pocket properties with hits' chemistries used in generation of ultra-large virtual libraries. Additional recent enhancement to the screening workflow involves the use of MolSoft's program RIDE that allows to efficiently screen the entire database to select the most promising leads, plus MolSoft's rapid, GPU-based docking tool RIDGE, as well as the rapid generation of conformers with their also GPU-based program GINGER.
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