Technologies & Services

We perform all major activities of drug discovery, from target validation through lead optimization and candidate selection. The majority of active projects fall into the categories of hit identification (screening), hit-to-lead, and lead optimization.

pipeline diagram

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Hit identification (Screening)

Small molecule hits are identified using a variety of experimental screening technologies, including:

  1. biochemical screens measuring a specific activity

  2. cell assays using primary cells and cell lines

  3. small model organism screens using high-content imaging

  4. fragment screening by surface plasmon resonance and nuclear magnetic resonance (NMR)

  5. site-directed disulfide trapping (aka tethering).

See examples of our projects in Programs & Projects.

High-throughput screening (HTS)

High-throughput screening (HTS) is a common approach for identifying compounds for further optimization. HTS uses robotic automation to allow testing of thousands to millions of compounds against one assay. Assays are miniaturized into 1-100 µl volumes and arrayed in plates containing ninety-six 1536-wells. The SMDC routinely uses 384-well format to test up to 400,000 compounds. Biochemical assay formats include measurements of fluorescence polarization, energy transfer, absorbance, luminescence, either as end-point or kinetic readouts. Cell-based assays can be based on whole well averages of a colorimetric, fluorimetric, or luminescent signal, or on high-content imaging of individual cells (bright field or fluorescence).

The SMDC has a recharge policy to facilitate development and executions of high-throughput screens. HTS projects tend to be highly collaborative and involve intellectual engagement from both the initiating labs and the SMDC staff scientists. Thus, contributions generally warrant co-authorship and staff often support grant submissions and fundraising efforts. Please do not hesitate to contact us with any questions and for screening costs. More details: High-throughput Screening Steps.

Compound Libraries

The SMDC houses more than 200,000 molecules, including libraries based on diverse compounds, approved drugs, and bioactives with known mechanisms of action (see Available Compounds). Libraries conform to the current standards for lead-likeness. For the diversity collection, molecules were selected to have at least four lead-like properties (MW < 350 Da; cLogP < 5; H-bond donors < 5; H-bond acceptors < 8; rotatable bonds < 8; polar surface area < 100A2). Compounds were also filtered to remove reactive functionalities (e.g., Michael acceptors and thiols) and known toxicophores (e.g., nitroxides), and promiscuous scaffolds have been flagged [e.g., 6,305 compounds contain chemotypes flagged as pan-assay interference compounds (PAINS) (Baell, 2010)]. More than 100 screens have been run with most of the compounds in this collection, providing a rich data set for identifying artifacts and potentially mechanisms of action. Our web interface SMDC HiTS (register here) also links to compounds found in ZINC and PubChem ChEMBL, enabling us to access data for hundreds of additional screens.

Fragment discovery

Fragment-based drug discovery (FBDD) is a complementary technology to high-throughput screening (HTS) and has proven successful for many drug targets that are recalcitrant to traditional functional assays. By this approach, fragments—compounds approximately one-half the molecular weight of a drug—are assayed using biophysical or structural approaches. Fragments shown to bind to the target are then structurally characterized and are optimized through linking or merging two fragments, or via addition of designed functional groups to a single fragment.


Fragment screening methodologies (Bulfer, et al, Making FBDD Work in Academia, in Fragment-based Drug Discovery, Lessons and Outlook, v 67, Methods and Principles in Medicinal Chemistry, Wiley-VCH, 2016)

Fragment screening is a special expertise of the SMDC, and projects are generally executed as funded collaborations. Routinely available technologies include surface plasmon resonance and disulfide trapping; second-harmonic generation (Biodesy), NMR, and crystallography-based screens are also possible. The current state-of-the-art in fragment optimization is structure-guided design, and therefore we recommend developing a path to high-resolution structural information in concert with fragment screening.


Tethering is a site-directed fragment discovery method wherein bespoke libraries of disulfide-containing compounds are screened for binding to a native or engineered cysteine residue. Fragments that are complementary to the binding site and have the proper geometry to react with the cysteine residue are stabilized. Mass spectrometry or functional assays are used to identify bound fragments. The tethering approach was first developed at Sunesis Pharmaceuticals. The SMDC continues to develop this unique, site-directed approach. (A Liquid Chromatography/Mass Spectrometry Method for Screening Disulfide Tethering Fragments, Hallenbeck, et al, SLAS Discovery, 2017, online Sept 2017; Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery, Hallenbeck, et al, Curr Top Med Chem, 2017, 17:4-15)


The fragment-screening libraries include 1,600 disulfide fragments synthesized at the SMDC and a 3,000-member fragment library optimized for surface plasmon resonance. The tethering and SPR libraries were selected for diversity, rule-of-three compliance, and three-dimensionality.

Hit-to-lead medicinal chemistry


Our chemists are available to collaborate on programs on a personnel-support basis and can support grantwriting and fundraising efforts. After a hit series is selected, we can move to initiate the synthesis of structural analogs. In general, the number of scaffolds taken forward into hit- to-lead chemistry depends on the how many have attractive properties and how many chemists are availabe to make analogs. As a rule of thumb, each scaffold requires a half-time to full-time chemist during the early stages.

We build a family of structurally similar compounds around the hit using several strategies. The primary data may suggest portions of the scaffold where structural changes modify function. Additionally, compounds are likely to have some sites that are easier to modify than others. The easiest way to scout for prospective structure-activity relationships (SAR) is to take advantage of commercially available materials. Web resources determine the availability of related compounds and allow searching based on substructure/scaffold or on overall similarity (e.g., Tanimoto similarity). Once materials have been received, quality control must be undertaken to assure the compounds have the correct mass and purity >95%. Its structure may also be confirmed by proton NMR. Pure compounds are then evaluated in the primary assay and key counter assays and secondary assays. Ideally, this SAR-by-catalog exercise will show that small changes to the compound structure alter the potency without changing the mechanism of action. Eventually, commercially available analogs will be exhausted, and compounds must be synthesized to address specific questions about the influence of certain electronic or steric factors on the activity.