CDoT has advanced small molecule drug discovery capabilities, including:
- Protein cloning, expression and purification from bacteria, insect, mammalian systems
- Structural biology (X-ray crystallography, NMR)
- Fragment based screening via NMR and SPR
- Mechanistic enzymology and biophysical hit finding validation
- Cellular imaging assay capabilities
- Medicinal, organic and computational chemistry
- Industry standard ADME capabilities
- Small molecule Quality Control and Purification
An additional strength is CDoT’s proximity to Broad’s scientific platforms, including CBTS, Proteomics, Metabolomics and Imaging. These relationships enable CDoT to incorporate the emerging technologies and novel genetic and disease mechanism insights being developed by these platforms.
Questions on working with CDoT can be emailed to CDoT-Collaborate@broadinstitute.org.
Protein Science and Structural Biology
CDoT’s Protein Science team has significant experience in the production, purification, and characterization of diverse protein types. The team utilizes bacterial, insect and mammalian expression systems to generate recombinant proteins, and a range of biophysical methods to characterize the purified proteins. In collaboration with the Biochemistry and Biophysics teams, these proteins are functionally characterized to establish the assays that drive the identification and optimization of lead compounds.
The Structural Biology team primarily employs its core expertise of macromolecular X-ray crystallography to provide key structural insights, often in the form of robust structure elucidation pipelines, to support our drug discovery projects. Where appropriate, the team also utilizes emerging and lower-throughput techniques, such as cryo-electron microscopy, to provide key project-enabling structural insights. The team collaborates closely with computational and medicinal chemists to analyze, design and test ideas via molecular docking and dynamics methods, as well as to find new chemical matter via virtual- and pharmacophore-based screening.
Biochemistry and Biophysics
CDoT's Biochemistry and Biophysics teams apply many different techniques to (a) identify potential ligands through screening (with core expertise in medium-throughput screening and fragment-based drug discovery) and b) provide detailed characterization of small molecules as they are optimized towards potential therapeutic application.
The Biochemistry team develops and utilizes biochemical assays to measure the functional consequences of compound binding a protein target. These assays are established at sufficient scale to enable high throughput screening and weekly iterative drug discovery testing. Also, lower throughput, higher resolution assays are established to determine a compound’s mechanism of action and drug-like properties. The Biophysics team applies a number of different techniques that measure the dynamics (kinetics) and energetics (thermodynamics) of binding a protein target, and in many cases can provide preliminary structural information. These techniques are used to identify initial chemical matter (via fragment based screening) or characterize how a compound binds its protein target.
The Biochemistry and Biophysics teams work in close collaboration with the Protein Science and Structural Biology teams to execute target based therapeutics projects. They also work closely with the CDoT Chemistry and Discovery Solutions and Systems teams to capture and efficiently display compound data for therapeutics projects.
Medicinal Chemistry is an integral part of all CDoT discovery projects, ranging from target validation up to compound optimization towards development candidates. Even though chemistry work within a drug discovery project is most often associated with starting after hit identification, at CDoT we recognize the importance of involvement of chemists early in projects to increase the chances of success.
As projects advance through the various stages of development, CDoT chemists play integral roles in:
- identification of prior art or tool compounds which can be utilized to validate assays and biological hypothesis
- collaborating with biologists to develop discovery project flowcharts
- establishing the best libraries for the project screens, ranging from HTS to fragment screens to DNA-encoded libraries
- establishing robust computational processes to conduct virtual screens incorporating machine learning
- hit validation and development of initial structure activity relationship (SAR)
- developing SAR strategies to optimize compounds towards project milestones, such as in vivo POC or development candidate selection
- determining molecules' inherent properties such as solubility or lipophilicity, measuring behavior in industry-standard ADME models, and characterizing bio-molecular interactions via an outsourcing model through our absorption, distribution, metabolism, and excretion (ADME) group
- supporting the Broad legal office's efforts to determine IP strategy
- identifying, setting up and managing close relationships to CROs
Translational Pharmacology meets the pharmacology needs of CDoT's drug discovery teams, typically involving cell-based assays in either the identification, optimization or characterization of new therapeutics. Translational Pharmacology partners with CDoT internal colleagues, including Discovery Sciences and Medicinal Chemistry, as well as with automation colleagues to develop reproducible and scalable assays.
Translational Pharmacology also partners with the talented scientists within the Broad community to help translate their novel discoveries into cell-based assays deployable to the drug discovery process. The team leverages existing and emerging technologies, such as high content imaging. Assays measure target engagement, pharmacodynamic modulation or biological effect that define decision points in the drug discovery process.
As programs progress, the team provides pharmacology insights into early animal studies with the goal of defining exposure-response relationships to inform in vivo activity and early tolerability assessments. Translational Sciences is also collaborating with Broad scientists to explore activity in disease relevant mouse models.
The Translational Pharmacology team also works with CROs with expertise in both common and unique rodent models to understand the pharmacokinetic profile of lead molecules and translate these discoveries into an understanding of activity in disease states.