UC San Diego

This dissertation describes studies into a new drug candidate discovery philosophy and its application to diseases. Over the last several decades, drug discovery has been focusing on one single target modulation. However, due to the high failure rate in drug development, a new philosophy that focusing on multiple drug-target interactions has gained escalating attention in both academia and industry. In this philosophy, drugs, especially

small-molecule drugs interact with multiple protein targets in their therapeutic concentrations.

In chapter 1, we explored the multi-target pharmacology of cancer drugs. We collected information about multiple targets for each cancer drug along with their experimental effective concentrations or binding activities from multiple sources. We showed that the majority of the cancer drugs had substantial multi-target pharmacology based on our current knowledge. The target subset can further be accentuated and personalized by patient sample-specific expression data. Besides analysis, we also built a web database for the public to access and easily explore the multi-target pharmacology of cancer drugs.

To gain a comprehensive multi-target pharmacology, we still need to study new protein targets to further extend the collection of known targets. In chapters 2 and 3, we studied a bacterial transcription factor, RfaH, which may be developed into a new antibacterial target. RfaH is a transcription processivity factor, belonging to a universally conserved transcriptional regulator, NusG/Stp5 family. Unlike other family members, RfaH exerts a distinct structural transformation during its binding to RNA polymerase. We first identified two key residues for the structural transformation through a combined structural and phylogenetic analysis. Then we screened a compound library and identified 3 first-in-class inhibitors for RfaH binding to RNA polymerase.

In chapter 4, we developed a novel target for Naegleria fowleri infection, primary amoebic meningoencephalitis (PAM). PAM is a rapid-onset brain infection in humans with over 97% mortality rate. Despite some progress in the treatment of the disease, there is no single, proven, evidence-based treatment with a high probability of cure. The target we developed was ERG2, an isomerase in the ergosterol synthetic pathway. We built a homology model of ERG2 and identified 4 amoebicidal chemicals with low human cell toxicity.