The unit consists of 20 scientists with drug discovery expertise, including experts in enzymology, high-throughput screening (HTS) assay development, pharmacology and high-throughput biology. Specifically the unit's main responsibilities are:

• Responsible for all key data required to achieve phase transition criteria
• Optimize and validate novel target assays and HTS screen proposals
• Complete screening campaigns and support hit-triage/analysis
• Carry-out key biological profiling activities to support medicinal chemistry unit hit-to-lead and lead
• optimization efforts
• Support early assessment/development of novel projects
• Provide expert drug discovery input to early target validation and novel screens
• Guide early assay development efforts in Disease Biology unit

Over the past decade, drug development failures attributed to poor pharmacokinetics (PK) have dramatically decreased from over 40% to around 10%. This is mainly due to the increasing availability of medium and high-throughput in vitro ADME screens (Absorption, Distribution, Metabolism, and Excretion) as well as an earlier focus on PK properties during the discovery process. The Pharmacology Unit collaborates closely with the Chemistry Unit during the hit-to-lead and lead optimization phases to ensure acceptable PK properties of the selected molecules that are designed, synthesized and purified by the medicinal chemists. This is initially accomplished using a battery of in vitro assays, followed by in vivo PK assessment of the compounds to evaluate oral bioavailability and exposure in plasma and target organs. We support the PK evaluation of novel compounds for the Dengue, Tuberculosis (TB) and Malaria drug discovery programs.

Our group is also responsible for the evaluation of compound activity in murine disease models of TB infection and Dengue viremia. Using PK modeling and simulation, and PK/PD analysis, we propose dose ranges for efficacy studies in early drug development. Finally, we apply allometric scaling methods to predict human efficacious doses using PK profiles.

In parallel, we have launched several research projects aimed at addressing some of the most crucial gaps in TB drug discovery. One aspect of anti-TB drug pharmacology, which has been largely neglected, is the understanding of drug penetration into the different types of pulmonary lesions and cavities. We are exploring the hypothesis that some TB drugs have poor lesion penetration properties and therefore do not reach their site of action effectively, contributing to long therapy duration, treatment failure and the alarming development of drug resistance. In collaboration with the group of Clifton Barry at the NIH , several Korean Hospitals and colleagues at Novartis-Basel, we study and model drug penetration into TB lesions in animal models and in TB patients using modern technologies such as Imaging Mass Spectrometry. Our ultimate objective is to develop, implement and validate practical assays for predicting the ability of small molecules to favorably distribute into TB lesions where the pathogens reside, thereby enabling the discovery of better and more effective drugs for TB.

The Pharmacology Unit is composed of three groups: In vivo Pharmacokinetics, headed by Suresh B Lakshminarayana; Bioanalytics, headed by Anne Goh; and Efficacy and Translational Research, headed by Maxime Hervé. Post-doctoral and PhD students receive training in Pharmacology on an ongoing basis.