Discussion

A high proportion of hit discovery activity for infectious diseases of the developing world uses phenotypic screening of target organisms grown in culture. Therefore, most compound series act through unknown mechanisms, requiring optimisation to be carried out using phenotypic activity alone. The talk covers two case studies on how the Drug Discovery Unit is working in partnership to carry out phenotypic projects.

We are working with multiple collaborators within the TB Drug Accelerator program to identify phenotypic screening hits and develop them into pre-clinical candidates for TB. To facilitate these activities we have analysed the properties of anti-TB agents and drugs. The talk will outline our findings and how properties of reported compounds compare with the parameters reported for ideal drug-like properties. In addition, the triaging process used to assess phenotypic hit series from both biological mode of action and chemistry developability angles will be described.

The second part of the talk describes a collaboration with Medicines for Malaria Venture (MMV) and its partners, which progressed a phenotypic screening hit against Plasmodium falciparum from the DDU’s focused kinase library, to a pre-clinical development candidate. Our experience emphasised the need to optimise drug-like properties in conjunction with improving phenotypic activity.