Structure Based Design, Inc.

Services and Products

Structure-based Drug Design- back to top

3-D structures produced by X-ray crystallography have become an integral part of the current drug discovery process. Structure-based drug design has proven effective in nearly all aspects of drug discovery and development. It provides the opportunity to glimpse the specific interactions of your molecules with the drug target you are working with. Based on the information viewed and analysis, chemists may move forward with more confidence in optimizing their leads.

Structure-based drug design can be used to optimize a lead's binding affinity, the specificity of its target while enhancing efficacy parameters, by eliminating unwanted properties and further contributing to yield more efficient candidates. Such strategies have the potential to shave off years and millions of dollars in the processes to identify a new drug candidate. SBD's structural biology service utilizes its experiences and proprietary technology to assist clients in employing structure-based drug design in their drug discovery.


1. Service for crystallization and structure determination

We provide gene-to-structure services in our laboratory. Our hands-on Ph.D. scientists draw on years of experience that allow them to select proper ways to express and purify a clients’ target proteins. It is our standard to prepare the best quality protein sample in purity, activity and stability for crystallization study.

All crystal structures at SBD will be determined with the data sets collected using synchrotron light sources. The quality of the final X-ray structure will match the publication requests for a crystal structure. Almost all protein crystals obtained at SBD have a higher resolution than the published crystal structure of same protein.

Our crystallographers have experience solving various drug targets including Kinases, Nuclear Receptors, Phosphodiesterases, Polymerases, Dehydrogenases, Proteases, RNA, Protein/protein complex and Protein/RNA complex et al.


2. Service for co-crystal structure determination with your leads

SBD has proprietary techniques in obtaining co-crystal structures in complex with leads via co-crystallization or soaking method. If the IC50 value of your lead is better than 50 μM, we will get the co-structure for you. Finding a compound in the co-structure not only depends on its affinity, but also on its solubility, specific interaction, and location of the binding site.  More important is the art of co-crystallization and soaking skills.  As discussed in the technology section, our experience in this field will enable the best chance at finding your compound in the co-crystal structure. We offer co-crystal structure services for hard-to-reach projects including tough protein targets and weak binders.

Location and refinement of our client’s compounds is the crucial step of a co-crystal structure. SBD will provide the highest quality co-crystal structure. The electron density map of the ligand in a complex structure will be well refined in order to precisely determine the position of all atoms.


3. Service models and packages

SBD’s service model is customer driven. We have flexible service packages to meet a client’s individual needs.

Service package I:

1.Crystallization of target protein provided by client
2. Determination of apo-crystal structure
3. Determination of co-crystal structures with ligands

Service package II:

1. Protein expression and purification at SBD
2. Multiple expression constructs of protein may be designed to obtain
    high resolution crystal
3. Determination of apo-crystal structure with a resolution of at least 2.5 Å
4. Determination of co-crystal structures with ligands

Service package III

1. Develop a high throughput protocol from protein preparation to co-crystal determination in order to efficiently obtain a number of co-crystal structures
2. Determine 20-30 co-crystal structures to support full processing of a client’s drug discovery project

Fragment-based Drug Discovery - back to top

Over the past few years a novel method for designing new leads in drug discovery has been developed as a fragment-based drug discovery (FBDD) approach. It uses X-ray crystallography to screen fragment libraries for a target protein. A protein crystal is soaked in a solution containing about 10 compound fragments, which range in size from 100-300 Daltons, for 3 to 24 hours. If a compound can form specific interactions with the protein, it will be determined in the co-crystal structure.

FBDD is developed based on the advantage of recent innovations in  computer technology, software, automation and synchrotron X-ray sources that have become generally available in the macromolecule crystallography field in recent years. The co-crystal structures can be determined in a high throughput manner. X-ray crystallography is fast becoming a screening tool.

FBDD has a number of attractive features compared to other high-throughput screenings. The approach will only locate compounds that bind specifically with the target protein. It is able to detect fragments with relatively low affinity, from 100 μM-10 mM, a range which may be difficult to identify using other methods. Both theoretical considerations and practical experience have demonstrated that the chemical space for ligand binding can be covered with ~1000 fragment compounds. table1

High-affinity compounds will be created by linking several low-affinity fragments together. Based on structure information, a suitable linker will be designed and it will maintain the binding interactions of the individual fragments. With the FBDD method, novel clinical candidates have been identified at several drug discovery companies in as little as 2-3 years. A growing number of pharmaceutical companies have employed FBDD in their drug discoveries. Many advanced leads and clinical drug candidates were developed by this approach.

Proprietary Methods to Achieve High-Hit Rate

At SBD, we have developed proprietary methods to get high-hit rates of fragments in crystallographic screen. The keys in achieving high-hit rates using the FBDD method are crystal resolution and stability of the target crystal in a soaking solution containing high concentration of fragments. Higher resolution structures not only helps locate more hits, but also in determining the specific compound that bound with the protein from the cocktail.  At SBD, it is our imperative to grow the highest resolution crystals to service our clients.

To get more hits of compounds, we usually soak the protein crystal with a compound cocktail containing 10 mM of individual compounds.  We have developed techniques to find a stable soaking condition for both compounds and crystals using our proprietary methods. The crystals can be moved from their original crystallization solution to a soaking solution where they are more stable with high concentrations of compounds.  We have successfully screened several drug targets with this method, and in such projects, we obtained a range of 5-8 % hits with soaked fragment cocktail compounds for a drug target.

Another option we utilize to obtain more hits is employing different crystal forms to soak with compounds. Protein molecules can typically be crystallized into several space groups. A protein molecule in different crystal forms has various contact surfaces. Some contacts in an individual crystal form may block compounds from accessing the binding site of interest. Thus, we employ multiple crystal forms to allow the compound to reach all possible binding sites, especially for sites targeted for new drug discovery purposes.

Fragment-based Crystallographic Screening Service

At Structure Based Design, Inc., we have built a platform using our large-scale protein expression, purification, proprietary technologies for co-crystal generation and high-throughput X-ray structure determination to offer fragment-based X-ray crystallographic screening services. This platform has demonstrated its ability to achieve high hit-rate fragments in co-crystal structures. The prepared crystals can be soaked with a client’s fragment library or SBD’s fragment library. We can solve three to ten complex structures a day, which can screen 30 to 100 compounds.

Feel free to contact us for a consultation and proposal for your project.

High Purity Protein Preparation - back to top

As a crystallographic service company, all protein samples at SBD will be purified to “crystallographic grade” purity. Protein products usually are purified with three different columns including affinity, ion exchange and size-exclusion. The purity of final products is better than 95% and can be directly used for crystallization and other high quality assays.

Specific activity and conformational homology of a protein are also major issues we consider during purification. We not only use general protecting reagents during the purification process, but also add various protection additives based on published literature about the protein. Protein characterization of the final product can be tested in house or at the local Bioscience Service Center using Electrophoresis, Bioactivity study, Reversed-phase HPLC, Dynamic Light Scattering, Mass Spectroscopy Instruments and BioCore.

Combining Fermenter, Akta Explorer and large sized chromatography systems in the laboratory, we can produce quantities of protein samples ranging from 10 mgs to a few grams.

Feel free to contact us for a consultation and quotation for your project.

Portfolio Drug Target Crystals - back to top

SBD's Portfolio Drug Target crystals are ready to launch your leads. They will greatly save time in reaching structure-based drug design. The high value co-crystal structures can be delivered within weeks after we receive a roughly 5 mg compound.

Our crystal Portfolio includes:

  • Inactive Aurora-A kinase ready-to-go
  • Active Aurora-A kinase
  • Full active Aurora-A kinase
  • Farnesoid X-activated receptor (FXR)
  • FXR with co-activator peptide
  • Human serum albumin
  • PAK1
  • PPAR gamma
  • ER
  • PR
  • AR
  • ERK2
  • P38a
  • Caspase 3
  • Human 17beta-Hydroxysteroid Dehydrogenase Type I
  • Ribosomal A-site RNA
  • HCV IRES subdomain IIa
  • L11-ribosomal RNA complex
  • RNA aptamer and its complex with target

New crystals of drug targets on the list are continuosly being added with SBD business development. The following crystals are under development at SBD, and will be available soon. Contact us for more details.

  • PI3K (p110g)
  • JAK2
  • HSP 90
  • HSP 70
  • PPAR delta
  • Kinase domain of human VEGF receptor 2
  • Ion channel