Moving from a completed screening campaign to a full chemistry program is a non-trivial task. In the Hit-to-lead phase we make sure that the identified compounds act through sound mechanisms, but also that an emerging SAR exists, that basic ADME properties are fulfilled and that an efficient chemical expansion can be made. We have a solid experience in finding the false positives, the promiscuous binders and the hits causing aggregation, as well as in efficient and high-quality pharmacological profiling of compounds. High quality chemical starting points dramatically improve the odds for a discovery project. We make sure that your hits are well characterized and worth the money.

iNovacia has a broad range of in-house techniques for profiling of HTS hits. We can ensure that hits act through sound mechanisms by confirming direct and reversible binding to the target, the stoichiometry of binding, thermodynamic profiling, compound induced modifications of target protein as well as identification of compound aggregation and promiscuous inhibition. Proper pharmacological effects are confirmed in secondary and functional assays.

iNovacia has a group of medicinal chemists with long experience from the pharmaceutical industry. With that background, we have brought with us a thorough understanding of the drug discovery process and the demands on small molecules that can serve as chemical starting points for further optimization. The hit-to-lead process at iNovacia has been streamlined and we apply a number of advanced technologies to accelerate the drug discovery process.

Our chemistry labs are well equipped for traditional synthetic medicinal chemistry as well as for parallel synthesis. Whenever possible chemical expansions of hits are performed by high throughput chemistry techniques, providing large number of compounds that explore a wide chemical diversity space in a quick and efficient manner. Typically, we design and synthesize several libraries containing a couple of hundred compounds, each as part of iterative steps to follow-up a promising hit.

Chemoinformatics is used to cluster compounds and define hit series, identify analogues and analyze structure-activity relationships (SAR). Both chemical similarity and sub-structure searching is employed, as well as 3D pharmacophore searching.

Computational chemistry design methods are regularly used to pose design hypotheses and build in drug-like properties. A well functioning inventory system for chemical building-blocks allows a rapid design-synthesis cycle.

The creation of binding hypothesis and SAR is greatly facilitated by the use of a central database for all chemical and biological data, from which data can be clustered, filtered and summarized.

We use software from Schrödinger and ChemAxon as primary computational chemistry tools.

A study in the mid-1990s showed that 40% of drug candidates failing in development were due to poor pharmacokinetic (PK) properties (Kennedy T. Drug Disc Today (1997), 2, 436-444.). Since then there has been a major effort in the pharmaceutical industry to implement ADME assays earlier in the drug discovery process, so that these properties can be optimized in parallel with activity to provide candidates with both good potency and drug-like properties. As a result, a more recent study has demonstrated that this strategy has indeed proved successful, and the number of drugs failing in development due to poor PK properties has reduced from 40 to 10% (Kola I., Landis J. Nat Rev Drug Disc (2004), 3, 711-715).

At iNovacia we have a battery of ADME profiling assays, such as solubility, plasma protein binding, lipid-water partition coefficients, CYP p450 inhibition, hERG binding, HepG2 cytotoxicity, and metabolic stability. Both high-throughput and more in-depth in vitro ADME assays are integrated in the Hit-to-Lead process and are offered as stand-alone services.