Viva Engine for Lead Discovery

basic information
Product description
Viva Engine for Lead Discovery (Ve-LeadTM
 
Lead discovery is an important early step in drug discovery projects. We provide lead discovery services for our customers with our proprietary Viva Engine for Lead Discovery platform based on ASMS screening technologies and several compound libraries.
● Several compound libraries (fragment, GPCR related, diversity)
● Different ASMS screening technologies
● World premier structure based drug discovery capabilities
● Biophysical methods for hit characterization (X-ray, SPR, NMR, Thermoshift)
● Bioassay/cell line/protein science capabilities
● Experienced medichem teams for H2L and LO
● Proven track record with screen-to-cocrystal in 6m, to lead in 1 yr, to candidate in 3 yrs.
 
Lead discovery is the first step in target based drug discovery and development process. Over the years, Viva has developed a highly effective process for lead discovery: The Viva Engine for Lead Discovery (Ve-LeadTM)
 
 
Viva Compound Libraries
 
Fragment Library
 
Fragment based drug discovery (FBDD) is an alternative strategy compared to traditional drug discovery. FBDD uses libraries with lower molecular weight. We have successfully provided FBDD services for a number of our customers’ projects, and many of the compounds discovered have advanced to leads and clinical candidates.
 
● Viva fragment library:
  ■ 2050 member from
     ◆ 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
 
GPCR related compound library
 

We have designed a unique fragment library, a GPCR related compound library and

a large diversity compound library, which is comprised of approximately 

100,000 compounds in total.

 
A collection of 6,500 low MW compounds with unique physico-chemical properties and structurally related to known GPCR allosteric modulators and general GPCR ligands.
● Novel allosteric modulators and general GPCR ligands from mining a collection of 5M unique compounds
● Lead-like or drug-like properties
● LCMS characterization
 
Diversity Compound Library
 
A collection of 100,000 low MW compounds with unique physico-chemical properties and structural diversity.
● Library compound selection
  ■ Diversity analysis of commercially available compounds (>5m)
  ■ MW 200-450 (ave 350)
  ■ LogP 0-5 (ave 3)
● LCMS characterization
● Screening
  ■ SEC-LCMS based ASMS, compound mixture format
  ■ Discovery of strong binding ligands (Kd < 10 uM)
  ■ Hits can be tested directly with biochemical/functional assays for H2L
● Application
  ■ Lead discovery of any soluble protein targets
  ■ GPCRs/ion channels/transporters stabilized by detergent or nanoDisc
 
Viva ASMS Screening Technologies
 
● ASMS (Affinity Selection Mass Spectrometry) technology
● Generally applicable to any soluble proteins and compound library mixtures
● Equilibrium solution binding, low uM compound concentration
● Label free, no need to immobilize protein, requires no extensive assay development
● Variable ligand affinity detectable
● Can be very high throughput
 
 
Viva hit characterization capabilities
● X-ray co-crystalliztion
  ■ Co-crystallization of soaking-in
  ■ Most experienced teams and largest capabilities 
● SPR
  ■ Kd measurement, competition and binding kinetics (kon/koff)
  ■ Experienced team, multiple equiupment and extensive capabilities
● Thermoshift 
  ■ Change of protein thermo melting curve upon ligand binding
  ■ More applicable to strong binding, difficult to detect weak binding
● NMR
  ■ Protein based NMR chemical shift change upon binding of ligand
  ■ Protein stable isotope labeling capabilities
  ■ Compound based NMR measurement of ligand binding
● Bioassay/cell line/protein science capabilities
  ■ Experienced bioassay teams and advanced equipment
  ■ Variety of cell line for cancer and CNS
  ■ Multiple protein expression systems
 
 
Experienced medichem teams for H2L and LO
 
● H2L, LO, and process route development
● Experience with non-covalent, covalent, and allosteric inhibition
● Experience with various target classes kinases, dehydrogenases, caboxylases, hydrolases, GPCR, & PPI
● Four compounds in clinical trials
 
Case study examples
Example 1:
 
 
 
Example 2:
Screening of client natural product extracts with SEC-ASMS
SEC-ASMS screening of full length EGFR and 3 full length GPCRs with natural product extract (~1000 components)
Identified uM hits from the natural product extracts for each targets
 
 
Example 3:
SEC-ASMS pilot screening for 3 targets (one phosphatase enzyme, one transmembrane receptor, one protein-protein interaction target)
8,800 Viva diversity library compounds screened with SEC-ASMS
uM hits found for each targets (hit rate 0.1-0.3%)
Limited SAR series can be observed for two hit series (for two different targets)
16 control compounds with KD/IC50 1nM-10uM were all detected with correct rank order
One control compound with double digit uM IC50 was not detected  
 
 
 
 
On a
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