GULCCDD Technology Core Capabilities and Strengths

Computer-Aided Drug Design Core

The CADD core leader Dr. Sivanesan Dakshanamurthy, has more than 22 years of experience in drug discovery and development, specifically in computer-aided drug design.

The CADD expertise, skills, and unique home-grown AI and computational technologies are particular assets. CADD core carries out specific tasks and provides complementary and synergistic expertise to effectively collaborate and align with several other center cores, thus maximizing productivity in drug discovery projects. They can interact with the biochemical compound profiling team that often seeks a broader depth of selectivity profiling.

The CADD core has novel technologies and a unique ability to capitalize on the target structural information to guide the synthesis of new analogs that test specific binding hypotheses and incorporate them into the other project team. Importantly, the homegrown technology assets with key pipeline characteristics can be quickly tuned or optimized for diverse drug discovery projects.

For example, our AI-driven methods prioritized high affinity, and selectivity candidates can be provided to the compound profiling team tasked with developing screening assays to profile the activity of compounds. This team interaction would reduce the cycle time of profiling compounds in vitro and in vivo. Such flexible intra-core activities within the LCCDD and inter-core cross-collaboration activities with other centers allow program drug candidates to be rapidly validated and moved into the candidate selection phase in coordination with other project teams.

We are uniquely positioned to provide the overall effort with the competitive advantage of applying specialized methods, including AI and electrostatics-driven methods for novel and complex targets not well-suited to more traditional approaches. Such targets are, undruggable, uncharacterized proteins and those not suitable for crystallization, intrinsically disordered proteins (IDPs), protein-protein interface, and protein allosteric surface target sites.

The CADD core technologies, implement risk-reducing and mitigation strategies early in the discovery process, thus providing significant added value and benefit to the drug discovery pipeline. The billion compounds database would allow a rapid exploration of chemical space to prioritize synthetic candidates and improve success rates in identifying optimized chemical matter.

  • Unique core competencies, scientific and technical expertise
  • Proven home-grown AI and computational technologies and optimized pipeline for hit-to-lead identification, lead hit expansion, and optimization.
  • Technology to predict ligand binding modes
  • Protocols for hit-to-scaffold assessment, go-no-go decisions to triage compounds
  • Technology to the rapid exploration of chemical space
  • Technology to handle undruggable and intrinsically disordered proteins
  • 3-D homology structure prediction
  • Structure-based fragment-to-lead optimization by linking, merging, and expansion approaches.
  • Drug-and-lead-like with ADME-T predictions using an AI-driven pipeline
  • Technology to predict target selectivity, affinity, and off-targets
  • Specific technology for drug repurposing 
  • Front-to-back-end multiple programming and scripting capabilities, state-of-the-art software and hardware capabilities, high-performance computing, and access to cloud resources.
  • Computational omics technologies for cross-collaboration

Biophysical Surface Plasmon Resonance Core

The SPR core led by Dr. Aykut Uren, MD.

The SPR Biophysical studies core provides technical expertise and instrumentation for surface plasmon resonance (SPR) technology. 

The core currently houses two Biacore instruments; a Biacore T200 and a Biacore 4000, both of which were originally acquired through S10 shared instrument grants from the NIH. 

The core can provide state-of-the-art SPR services to characterize protein-protein, protein-nucleic acid, and protein-small molecule interactions. Since SPR allows for the discovery of small molecules that can directly bind to a target protein, it does not require structural information of the target protein obtained by crystallography or NMR. Even intrinsically disordered proteins that are considered undruggable can be successfully utilized in SPR experiments for small molecule or drug screening experiments.

We have been providing SPR services to investigators at Georgetown University, at other academic institutions, and biotechnology companies in the United States and other countries with these instruments. Over the past 18 years, we have performed more than 2000 SPR experiments that included multiple drug discovery projects. We have identified many novel hit compounds for target proteins and several of these projects were advanced to lead optimization and SAR studies and phase 2 clinical trial.

  • Surface Plasmon Resonance Technology Service with Biacore T200 and Biacore 4000
  • Small molecule screening for direct binding to target proteins.
  • Label-free binding affinity (KD, ka, kd) analysis between two molecules (protein-protein, antigen-antibody, DNA-Protein, RNA-Protein, small molecule-protein).
  • Label-free thermodynamic analysis of molecular interactions.

Cancer Cell Biology Core

The objective of the Cancer Cell Biology (CCB) operational pipeline is to test the activity of small molecule candidates.

The CCB provides expertise in multiple cancer cell biology technologies ranging from molecular and cellular biology to state-of-the-art single-cell and spatial biology approaches and cell, organoid, zebrafish, and rodent modeling.

Combined with in-house expertise in Pathology, these approaches will enable CCB to aid in advancing any hit-to-lead candidates to IND, enabling studies by intra- and -inter-CBC center cross-collaborations.

  • Cancer signaling mechanisms
  • Epigenetic mechanisms
  • Cancer cell-brain organoid models
  • Establish target mechanism of action or new small molecule mechanism of action
  • Wnt/Shh signaling networks
  • Intestinal and CRC-derived organoids
  • CRC PDX models
  • Medulloblastoma spheroid cultures