The research conducted within the Synthetic Biologics Core (SBC) Facility has a dual role: 1) generate chemical biology tools and drug candidates for molecular targets identified by NCI research groups and 2) develop novel effective methods and tools for more effective molecular discovery. Chemical biology tools for studying protein functions have many advantages over applications of genetic approaches for studying protein functions. However, wide use of chemical probes is hampered by the difficulties in their generation and characterization. Because the majority of cancer drivers and proteins regulating immune responses to tumors are considered non-druggable by small molecules, the focus of SBC has been on these high hanging fruits of drug discovery. We hypothesize that one of the reasons in our inability to target these difficult targets is that we are not searching in the right part of the chemical universe. The total number of on-the-shelf unique compounds available in the commercial market is in on the order of 100 million. This represents only a microscopically small fraction of the drug-like small-molecule space, which has been estimated to be on the order of at least 1063 possible structures. We are trying to test if the expansion of the accessible part of the chemical universe could allow for the discovery of ligands for most difficult protein targets. During the past four years, our facility has switched to mostly computational approaches because they allow for exploration of a very large number of diverse compounds. Virtual screens have become lately one of the primary methods in early leads identification for several reason: Accuracy of docking software including algorithms evaluating binding energy have improved significantly; sufficient computational resources (clusters, GPUs, cloud computing) have become available; significant advances in protein structure determination technologies have been made; and large virtual libraries of synthesizable compounds have been developed.
SBC combines modern computational methods with unique computing resources available at NIH to develops new technologies that not only simplify and accelerate identification of chemical probes, but also boost the success rates by increasing the accessible part of chemical universe. SBC is involved in generation of large databases of synthetically accessible compounds while developing methodologies for mining in these vast databases for ligands of proteins that are of interest to our collaborators.
To request services from this Facility, you must contact the Facility head at firstname.lastname@example.org .
Exxact Linux server
ICM-Pro license, RIDE license, RIDGE license (Molsoft)
- Patel, H.; Ihlenfeldt, W. D.; Judson, P. N.; Moroz, Y. S.; Pevzner, Y.; Peach, M. L.; Delannee, V.; Tarasova, N. I.; Nicklaus, M. C., SAVI, in silico generation of billions of easily synthesizable compounds through expert-system type rules. https://www.nature.com/articles/s41597-020-00727-4 Sci Data 2020, 7 (1), 384.
- Bonilla, P. A.; Hoop, C. L.; Stefanisko, K.; Tarasov, S. G.; Sinha, S.; Nicklaus, M. C.; Tarasova, N. I., Virtual screening of ultra-large chemical libraries identifies cell-permeable small-molecule inhibitors of a “non-druggable” target, STAT3 N-terminal domain. Frontiers in Oncology 2023, 13.
- Lu X, Sabbasani VR, Osei-Amponsa V, Evans CN, King JC, Tarasov SG, Dyba M, Das S, Chan KC, Schwieters CD, Choudhari S, Fromont C, Zhao Y, Tran B, Chen X, Matsuo H, Andresson T, Chari R, Swenson RE, Tarasova NI, Walters KJ. Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.https://www.nature.com/articles/s41467-021-27570-4 Nat Commun, 2021 12(1):7318-7335.
- Judson, P. N.; Ihlenfeldt, W. D.; Patel, H.; Delannee, V.; Tarasova, N.; Nicklaus, M. C., Adapting CHMTRN (CHeMistry TRaNslator) for a New Use. J Chem Inf Model 2020. 60, 7, 3336–3341
- Song, R; Nicklaus, M; Tarasova, N.I. Correlation of binding site properties with chemistries used for generation of ultra-large virtual libraries. ChemRxiv 2023, 2023. https://chemrxiv.org/engage/chemrxiv/article-details/6436f59808c86922ffdbd59a