Genes To Leads

Genes To LeadsTM is a customizable and integrated suite of services that accelerate drug discovery. Starting with a customer’s gene sequence (or protein sequence), it delivers selective hits (potential lead compounds) in as little as 60 days.

Proven track record of success:

The Genes To LeadsTM service incorporates Sapient’s proprietary DynaPharmTM technology - a system that extracts predictive drug shape information from flexible pharmacophore constructs derived from analysis of the dynamic 3D-structures of protein drug-targets and their anti-targets (structurally similar proteins against which the lead compounds must show good selectivity).

Sapient’s unique and proven in silico screening methods using search queries based on DynaPharmsTM delivers highly target-specific compounds. Our novel computational screening technology has been successfully applied to a variety of therapeutic drug targets. Genes To LeadsTM provides a cost-effective, highly efficient and rapid means for pharmaceutical and biotechnology companies to exploit the proliferation of new targets brought about by the genomic revolution in discovering new therapeutic treatments.  The technology permits the rapid generation of non-peptide, small molecule drug leads in 60 – 120 days, in multiple chemical scaffolds, with efficiencies in synthesis and testing that are approximately 1,000-fold greater than other lead discovery approaches.

Genes To LeadsTM Applications:

Genes To LeadsTM may be used as an independent source of initial drug leads, as a complement to existing in-house High-throughput screening (HTS) - providing compound pre-selection and overflow capacity, or as a reliable fallback option for drug targets not well suited to HTS.  The technology is extendable to so-called “fragment based drug discovery”, wherein this technology may be used to narrow down the initial set of fragments to be used in crystallographic or nmr based screening, significantly reducing the cost and time required for such screening.

Genes To LeadsTM accelerates virtual screening:

The Genes To LeadsTM process combines proprietary computational prescreening of millions of potential drug-lead structures incorporating differential structural information derived from the dynamic conformations of protein drug targets and their structurally similar “anti-targets”, with the actual laboratory screening of only about 200-400 compounds. Typical hit rates average about 10% and have ranged from a low of 2% to a high of 22% over 18 diverse targets. Compounds may be selected from among approximately ten million commercially available compounds, from millions of compounds in Sapient Discovery’s virtual CombiLibTM libraries built around attractive chemistries or scaffolds, or from the collaborative partner’s in-house compound collections.

Unlike automated docking methodologies, which require a high resolution X-ray structure and only work for enzymes, our Genes To LeadsTM technology does not require an X-ray structure of the target and works equally well for protein-protein interactions including some, though not all, GPCR’s, as well as for enzymes.  The technology is extendable to fragment based screening wherein the first set of fragments may be identified in the absence of the initial x-ray structure of the protein target further accelerating lead identification in this type of screening.

Key Aspects of Genes To LeadsTM

  • Permits rapid generation of non-peptide, small molecule drug leads in 60 – 120 days;
  • Yields multiple chemical scaffolds and facilitates exploration of new chemical scaffolds inexpensively;
  • Work for enzyme, protein-protein interaction, and GPCR targets;
  • Incorporates differential structural information from drug targets and “anti-targets” thereby enabling selectivity incorporation in the initial screening stage;
  • Requires laboratory screening of only about 200-400 compounds – saving synthesis and biological screening costs;
  • Typical hit rates average about 10%;
  • Proven to work repeatedly - 18 diverse targets and over 35 issued composition of matter patents;
  • Provides a practical way to exploit molecular diversity by computationally prescreening millions of real and virtual molecules prior to selection for synthesis and testing.

The computational methods developed and employed by Sapient Discovery have been used to produce a number of successful lead compounds including an orally-active, long-acting selective sub-nanomolar endothelin receptor antagonist (Thelin®) recently recommended by a special committee for approval in Europe for treatment of pulmonary arterial hypertension, nanomolar PTP-1B inhibitors that exhibit prolonged glucose lowering activity and obesity control in a diabetes animal model, anthrax lethal factor inhibitors that prevent macrophage destruction – the lethality causing event in anthrax infection, and other drug-target selective molecules in the angiogenesis, cancer, bacterial and viral disease, and inflammatory disease areas.

DynaPharmTM Generation:

As part of Sapient Discovery's expert consulting services, molecular dynamics simulations are used to derive a 3-D dynamic model of a solvated drug target protein surface, followed by application of proprietary algorithms to derive flexible pharmacophore templates (also termed, DynaPharmTM Templates).  The DynaPharmTM templates describe the chemical features and their flexibility that are required for binding to a drug target.  Our DynaPharmTM based drug discovery services feature a database containing the three-dimensional structures of several million compounds that are computationally screened to identify bioactive molecules that mimic the shape of the DynaPharmTM Templates.  A 3-D flexible search algorithm is used which allows for conformational changes in the compounds. 

Virtual Screening:

Sapient Discovery’s consulting services utilize a computational approach that has a number of advantages over high-throughput screening (HTS) in that a large virtual library of commercially available chemicals or virtual combinatorial chemicals may be computationally pre-screened rapidly to select molecules with likely bioactivity. Following the computational screen, the actual number of molecules that need to be physically acquired and assayed is typically in the 200-300 compound range.  This represents a two to three order of magnitude reduction in the number of compounds typically screened, which translates into dramatically increased speed of initial lead Discovery and step-by-step cost reductions in compound acquisition/synthesis and screening.  The technology may be used to provide an independent source of initial drug leads, or may be used to complement existing in-house HTS by providing prescreening information, overflow capacity, or a fallback option for targets that may not be amenable to HTS.  In terms of time, our screening takes days to weeks instead of months as one normally expects in HTS.  The DynaPharmTM technology can also be used to select compounds for “fragment based” drug discovery further reducing the cost and time to elucidate possible leads from crystallography and nmr methods.

Drug-like Filtering:

Several physicochemical properties are computed for virtual compound hits for use in “drug-likeness” filtering. Sapient Discovery uses proprietary and proven algorithms to efficiently filter virtual compound hits to insure  that the resultant final list is as drug-like as possible.  In addition certain specific filters can also be incorporated for customer projects to best suit the specific target and biological screening protocols. 

Protein-protein Interactions:

Sapient Discovery’s lead generation technology is very well suited for finding antagonists of protein-protein interactions.  The technology works with the knowledge of either the structure of the ligand protein or of the receptor.

Protein-protein docking:

Applicable to antagonist design or studies of certain structure-function or mechanistic relationships, Sapient Discovery can carry out protein-protein docking in rigid and flexible mode and decipher the individual interactions between the accessory proteins.

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