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Fragment Based Lead Generation

Fragment-based Drug Design (FBDD) is an alternative approach to drug discovery that starts from small molecule fragments and leads to novel hits and drug leads. The FBDD approach typically involves testing fewer compounds, generating hits with wider scope for development (mw & Log P), and providing a complementary strategy to HTS.

Viva provides comprehensive FBDD services to our clients. Our FBDD team is headed by Dr. Shawn Cheng, Dr. Zhixiong Ye, Dr. Derek Ren, and Dr. Cheney Mao. Dr. Shawn Cheng is an expert in affinity screening, compound library management and mass spectrometry with 13 years of experience as senior drug discovery scientist at Abbott Laboratories. Dr. Zhixiong Ye is an expert in discovery chemistry with 14 years of drug discovery experience at Merck. Dr. Derek Ren is an expert in discovery biology with 10 years drug discovery experience at Pfizer. Dr. Cheney Mao is experienced in structure-based drug discovery in anti-HIV and anti-cancer area for 7 years while working at Hughes Institute.

We provide FBDD services with a suite of technologies to address different needs of our clients. Viva's FBDD platform is focused on X-ray crystallography, mass spectrometry binding analysis, NMR protein labeling methodology, as well as SPR, thermo-shift, and bioassay measurements.

Viva's FBDD Approach:

▩ Fragment Library of Diverse Structures

In-house collection of 2,000 low MW compound with unique physico-chemical properties and structural diversities. Clients are also welcome to provide their compounds for testing.

■ 2000 members
○ Commercial vendors (>5)
○ Internal synthesis
○ Other sources
■ Diverse structural elements
○ Analysis of know drugs, candidates and leads
○ Fragment scaffolds
■ Physico-chemical properties
○ Rule of 3
○ Solubility: important for X-ray and NMR
○ LCMS properties and sensitivity

X-ray Crystallography Based Techniques

Single or small mixtures of compounds with soaking-in or co-crystallization
 
Features
○ Detailed information about protein structure, ligand binding site and binding mode
○ Can detect weak ligands
○ Requires protein crystallization
Timeline
○ Preparation for crystallizable protein: 1-3 months
○ Crystallization trial and structure determination
○ Soaking and co-crystallization: several weeks

Mass Spectrometry Based technique

Identifies non-covalent protein-ligand interactions
 
Features
○ Generally applicable to any soluble proteins
○ Equilibrium solution binding, low uM compound concentration
○ Label free, no need protein immobilization or assay development
○ Variable ligand affinity detectable
○ High throughput 
Timeline
○ A few days to rank order affinity for small number of compounds
○ 2-4 weeks for large number of compounds (100 to >1000)
 

Surface Plasmon Resonance (SPR)

Label-free screening and ligand biding study

Comprehensive characterization:

    Binding kinetics, affinity, and specificity etc.

Protein NMR Spectroscopy

High-yield production of labeled protein for NMR

Thermo-shift assay and activity assays

Medichem for fragment expansion