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Pathway-Centric Structure-Based Multi-Target Compound Screening for Anti-Virulence Drug Repurposing.

TitlePathway-Centric Structure-Based Multi-Target Compound Screening for Anti-Virulence Drug Repurposing.
Publication TypeJournal Article
Year of Publication2019
AuthorsXie L, Xie L
JournalInt J Mol Sci
Volume20
Issue14
Date Published2019 Jul 17
ISSN1422-0067
KeywordsAnti-Bacterial Agents, Drug Design, Drug Discovery, Drug Repositioning, Humans, Molecular Docking Simulation
Abstract

The emergence of superbugs that are resistant to last-resort antibiotics poses a serious threat to human health, and we are in a "race against time to develop new antibiotics." New approaches are urgently needed to control drug-resistant pathogens, and to reduce the emergence of new drug-resistant microbes. Targeting bacterial virulence has emerged as an important strategy for combating drug-resistant pathogens. It has been shown that pyocyanin, which is produced by the phenazine biosynthesis pathway, plays a key role in the virulence of infection, making it an attractive target for anti-infective drug discovery. In order to discover efficient therapeutics that inhibit the phenazine biosynthesis in a timely fashion, we screen 2004 clinical and pre-clinical drugs to target multiple enzymes in the phenazine biosynthesis pathway, using a novel procedure of protein-ligand docking. Our detailed analysis suggests that kinase inhibitors, notably Lifirafenib, are promising lead compounds for inhibiting aroQ, phzG, and phzS enzymes that are involved in the phenazine biosynthesis, and merit further experimental validations. In principle, inhibiting multiple targets in a pathway will be more effective and have less chance of the emergence of drug resistance than targeting a single protein. Our multi-target structure-based drug design strategy can be applied to other pathways, as well as provide a systematic approach to polypharmacological drug repositioning.

DOI10.3390/ijms20143504
Alternate JournalInt J Mol Sci
PubMed ID31319464
PubMed Central IDPMC6678309
Grant ListR21 TR001722 / TR / NCATS NIH HHS / United States
R21TR001722 / TR / NCATS NIH HHS / United States
R01LM011986 / LM / NLM NIH HHS / United States
R01GM122845 / GM / NIGMS NIH HHS / United States