Compound Libraries Available for High-Throughput Screening (HTS) in the Stanford HTBC
Diverse Collection: Our compound library contains over 130,000 diverse compounds from ChemDiv (50K), SPECS (30K), and Chembridge (23.5K). Since our emphasis is on diversity, most of our compounds are not from combinatorial nor directed libraries, although we do have 10,000 combinatorial compounds from ChemRX and 10,000 compounds from the Kinase directed set from ChemDiv (Mitotic Kinase targeted library info, Tyrosine Kinase targeted library info).
Known Bioactives and FDA Approved Drugs: For assay validation and smaller screens we have libraries of known modulators/FDA approved drugs including; the Library of Pharmacologically Active Compounds (LOPAC1280), the NIH Clinical Collection (NIHCC), and the NCI DTP. We have recently added three additional Drug libraries; the Microsource Spectrum, and the Biomol (now Enzo Life Sciences) ICCB Known Bioactives and FDA Approved Drug Library.
Compound Fragment Libraries: For fragment screening (Surface Plasmon Resonance-SPR on a Biacore T200) in collaboration with the PAN facility, the HTBC has obtained 5000 compound fragments from Maybridge and Life Chemicals. The HTBC has the Maybridge Ro3 Diversity Fragment Library (2500 compounds, Flyer, How Library was generated) and 2500 selected compounds from Life Chemicals Fragment Libraries.
The HTBC screens one compound per well in a 384-well microplate format (~500 384 well plates) except the LOPAC, Microsource and Biomol libraries which are screened in a 7 point titration (qHTS).
List of Available Screening Compounds
Discovering New Therapeutic Uses for Existing Molecules.
Online Tools: For Compound Re-orders search here (emolecules.com) to see which vendors have your compound in stock. Also, look for your hit in other screens at PubChem or download Scaffold Hunter. Convert your ID to CID or other ID here (UC Davis). Website with tons of links to online tools--Virtual Ligand Screening.
Is your hit a promiscuous hit compound? Check it here (Scripps)! Is your hit real? Review this paper and This one.
Overview of how compounds were selected (Properties of current library Powerpoint PDF):
The initial 30,000 compounds from Specs were selected on the following criteria, with the help of Anang Shelat of R. Kip Guy's lab fomerly at UCSF. Anang used InHouse models and the commercially available, Scitegic Pipeline Pilot, to perform the computational analysis. The 50,000 compounds from ChemDiv were selected similarily by Brian Wolff in collaboration with Jan Williams, formerly at the Small Molecule Discovery Center-HTS Division, and James Wells at UCSF. Additionally, we purchased a 10,000 compound Kinase-directed library from ChemDiv with funds from a generous donation by a private foundation. For additional information on screening compounds see PubChem.
(A) Using SD files (structure files containg over 200,000 compounds available) from Specs, molecules were passed through a standardization procedure: charges were cleared and set to formal charge, salts were stripped, certain topologies (such as nitro, sulfate) were canonicalized, and a canonical tautomer was selected.
(B) These molecules were passed through a Lipinski "Rule of Five" filter: Num_Atoms > 0 AND (N_count and O_count <= 10) AND (100 <= MW >= 500) AND (Num_H_Donors <= 5) AND (-5 <= AlogP <= 5) AND All Organic Atoms (salts were stripped earlier, so they are not considered here). This resulted in about 150,000 molecules.
(C) These modified Lipinski molecules were ionized using an InHouse pka model and filtered based on formal charge: -3 <= FC <= 3. Nearly all the molecules passed.
(D) The molecules were then passed through a REOS (Rapid Elimination of Swill) filter (eliminating functional groups deemed reactive by literature and consultations with medicinal chemists). This step eliminated another 30,000 molecules.
(E) A Bayesian categorizer was used to distinguish the Specs molecules from UCSF's InHouse Library (input variables: chemical fingerprint and calculable physical properties). The compounds from Specs were annotated with this score (lower score = most unlike InHouse compounds), thus creating a diversity spread of the library.
(F) A randomized selection of the ~120,000 compounds was ordered to comprise the inital 30,000 compounds of the HTBC's library.
References:
Christopher A. Lipinski, Franco Lombardo, Beryl W. Dominy, Paul J. Feeney "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings", Adv. Drug Delivery Rev., 2001, 46(1-3), 3-26. PMID 11259830.
Brian Y. Feng, Anang Shelat, Thompson N. Doman, R. Kip Guy, & Brian K. Shoichet "High-throughput assays for promiscuous inhibitors", Nature Chemical Biology, 2005 Aug;1(3):146-8.
James Inglese, Douglas S. Auld, Ajit Jadhav, Ronald L. Johnson, Anton Simeonov, Adam Yasgar, Wei Zheng, and Christopher P. Austin "Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries", PNAS, 2006 Aug.1; 103(31):11473-11478.
