Case Studies

In silico Guided Hit-to-Candidate


A key principle in the efficient progression of compounds from Hit to Candidate is effective decision making. StarDrop enabled the project team to:

  • Rapidly focus resources on low risk chemistry
  • Identify potential risks and prioritise in vitro ADME studies
  • Analyse in vitro ADME results in order to select optimal chemistry for in vivo study

As a result of this process, the project goals were met and clinical trials are now underway.

Today, drug discovery teams across the pharmaceutical industry know the importance of ADME data for selecting those compounds with the highest chance of success as drug candidates. Making the right decisions is crucial and depends on having the right data. However the right data are only generated if the right questions are asked.


The ambitious target set by a client was to identify a novel drug candidate for a cardiac target and progress the chosen molecule to Phase I clinical trials within 2.5 years. Initial hits were obtained against the target and the chemistry program focused on a limited number of related chemotypes.


Phase 1 – In silico

StarDrop enables a project team to objectively score compounds for their likelihood of success against their target product profile. By defining a scoring profile based upon in vitro potency against the target and predicted ADME properties, it was possible to identify those areas of chemistry space with the highest chance of success.

Phase 2 – In vitro

Having identified compounds most likely to meet the target product profile, and expanded the chemistry around the lead chemotype, an in vitro ADME screening cascade was put in place. The principle ADME risks predicted for the compounds were poor aqueous solubility and a high risk of Phase I metabolism resulting from the high logP for many of the compounds.

Once in vitro testing had identified compounds with a high likelihood of showing efficacy from oral doses, in vivo work in animal models of disease and PK studies in support of these, and future toxicology studies, were initiated. The range of in vitro studies was expanded on key molecules to help answer questions arising from the in vivo work and to further assess potential ADME-related risks for progression to man. These studies included incubation with human cytochromes P450 to assess likely drug-drug interactions, testing for potential interaction with the active efflux protein P-glycoprotein, measurement of plasma protein binding and comparison of metabolism in hepatocytes from human and animal species.


Phase 3 – In vivo

A pharmacokinetic profile which allows a drug molecule to rapidly reach its target from the site of administration, and remain there for long enough at sufficient concentrations to be effective, is essential for success. The Candidate molecule showed some indication of having a slow absorption profile, which may reflect the limited solubility anticipated for this chemotype from the in silico and in vitro analyses. This may explain the increased inter-animal variation in plasma concentrations seen after oral dosing when going from rat to dog; where the formulation volume becomes lower as a proportion of gut volume. Hence, it is anticipated that a number of formulations may need to be tested to obtain the optimum for studies in large animals and man.