16. Automated Identification of Potential Multi-Target Ligands

Project Description

Drug candidates designed to target single macromolecule targets often fail in showing expected safety and efficacy in vivo, although they looked promising when tested in vitro. It is because living organisms have alternative pathways that can compensate the action of a drug molecule on the intended macromolecule target. It is especially true for complex diseases, like cancer and diabetes, whose underlying mechanism involves multiple pathways, genes, and proteins. Therefore, there is a great interest in developing a drug that simultaneously targets multiple proteins. This has led to a new drug discovery paradigm called “polypharmacology”. The proposed study is to write a script(s) that identify potential multi-target drug candidates from PubChem.

Methods

Assuming that we are interested in finding “dual-target” molecules that target two proteins A and B, this project will take the following steps:

1. Search PubChem for assays that were performed against each of targets A and B.
2. Retrieve compounds tested to be active in *both* assays retrieved from (1). These are known dual-target ligands for A and B.
3. Search PubChem for compounds that are structurally similar to the molecules retrieved in (2). These are potential dual-target ligands for A and B.
4. Retrieve bioactivity data of the potential dual-target ligands [retrieved from (3)] against the targets A and B.
5. Prioritize the potential dual-target ligands [retrieved in (3)] based on their bioactivity data [retrieved in (4)].
   • If a molecule has been tested to be active against both targets, they are “known” dual-target ligands and already used as a query in (3). it is not necessary to test them against the same targets again, although some of them may be included as reference compounds in further screening to check the consistency of new screening data with the existing assay data.
   • If compounds are known actives against one of the two targets but have not been tested against the other, these compounds may be considered as high-priority compounds for subsequent tests.
   • If compounds are known inactives against either of the two targets, they may be regarded as low-priority compounds or excluded from consideration for further screening.

In this protocol, it assumed that we are interested in dual-target ligands, but we can extend this idea to drugs that target more than two proteins, or to selective drugs that can bind to one target but not to another target(s).