Lead Optimization Services

Sapient Discovery has the ability to work with suitable partners in lead optimization projects extending the structure based design capabilities.  The lead optimization services are offered on a fee-for-service mode utilizing the biological and chemistry capabilities of customers. 

The core technologies accessible from Sapient Discovery for lead optimization are:

  • Structure Based Design;
  • Protein Informatics;
  • X-ray Crystallography;
  • Focused Virtual Library Design;
  • Quantitative Structure Activity Relationship Development and
  • Computational Prediction of ADMET Parameters:

Our computational chemistry capabilities could help in lead optimization in the following main areas:

X-ray Crystallography: 

Our co-crystallization capabilities could be harnessed to provide very crucial feedback for modeling and chemistry and for structure based optimization by:

  • Confirm the mechanism of binding (competitive vs. non-competitive, vs. allosteric) by providing actual three-dimensional snap-shot of the binding. 
  • Providing exact modes of binding thereby providing direction to selection of suitable initial hits for optimization and ruling out possible non-binders.
  • Pinpoint individual atomic interactions of the target with the inhibitor  by providing exact binding modes as well as conformational status of inhibitor and the protein.
  • Identification of potential points to exploit on the target protein molecule for building additional potency.
  • Help in refining structure-based computational design and facilitating efficient SAR development
  • Sapient Discovery has the ability to provide full service X-ray crystallography from cloning of our target all the way to structure determination of the customer’s target with their inhibitors.
  • Facilitates early identification of promiscuous inhibitors thereby saving costs incurred in expensive biology experiments.

Protein Informatics:
Target-Anti-target analysis for building selectivity in the lead optimization process:

In this case our protein informatics experience and structure based design technology is effectively used for:     

  • Accessing Augmented Protein HomologyTM models of anti-targets in order to build selectivity and reduce cross-reactivity thereby reducing potential toxicology issues during pre-clinical development;
  • Exploit target-specific amino acid side chain and structural differences by target-anti-target comparisons;
  • Survey protein topography for inhibitor design favoring the selected target rather than the anti-target and  
  • Our StructureBankTM provides access to over 5000 high quality protein structures which could be used in conjunction with other public domain crystallographic structures to select possible anti-targets in the lead optimization projects.

Focused Virtual library Design:

At Sapient Discovery we have extensive virtual library modules, CombiLibTM, which are comprised of drug scaffolds designed based on ease of synthesis.  These library modules could be extended for each project with its own proprietary scaffold keeping in mind ease of synthesis, drug-likeness and existing structure-activity data.  In addition we also provide the following:

  • Design focused libraries with chemistry input;
  • Rapid in silico ranking of focused virtual libraries;
  • Predict  and rank order potency by means of free-energy calculation (deltaG) and
  • Prediction/ranking of binding affinity and hence in vitro potency for enzyme targets.

In order to better meet the customer needs for diverse, drug-like hits that improve coverage of chemical property space, Sapient Discovery has formed a partnership with a new medicinal chemistry company, Focus Synthesis LLC.  In the creation and synthesis of libraries idealized for the DynaPharmTM approach, Sapient Discovery will include the diverse, optimally distinct, and “drug-like” building blocks that Focus Synthesis designs using cheminformatics and intelligent database mining.  With this approach,   the customer gets the ability to improve the strength and breadth of their IP position by expanding on unique hits and leads identified in libraries that combine the power of Sapient Discovery and Focus technologies. 

Quantitative Structure Activity Relationship Development: 

  • Compute and predict crucial physico-chemical properties of novel inhibitors;
  • Establish quantitative docking model or models based on molecules for which binding constants have been determined;
  • Compare and contrast the binding of the inhibitors with targets and the corresponding anti-targets with specific computation of binding energies;
  • Correlate predicted free energy of binding with actual binding constants for these molecules as determined by biological assays and
  • Use model to predict binding constants of  newly proposed compounds to be synthesized, thereby reducing the cost for unnecessary syntheses;
  • Iteratively  refine the model as more X-ray  crystallography and biology data becomes available.

Computational prediction of ADMET parameters:

  • Evaluate drug likeness of both virtual libraries designed, synthesized compounds as well as literature based data using algorithms developed in-house and
  • Cell permeability predictions.

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