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.
NIH HPC
Exxact Linux server
ICM-Pro license, RIDE license, RIDGE license (Molsoft)
To request services from this Facility, you must contact the Facility head at nadya.tarasova@nih.gov .