NICEdrug.ch, a workflow for rational drug design and systems-level analysis of drug metabolism

Elife. 2021 Aug 3;10:e65543. doi: 10.7554/eLife.65543.

Abstract

The discovery of a drug requires over a decade of intensive research and financial investments - and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

Keywords: E. coli; P. falciparum; computational biology; drug clustering; drug metabolic fate; drug similarity; enzyme inhibition; human; ligand-based drug discovery; medicine; nutraceuticals; systems biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / chemistry
  • Antimetabolites, Antineoplastic / metabolism
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment
  • Databases, Pharmaceutical
  • Drug Design*
  • Drug Discovery / methods*
  • Drug Repositioning*
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / metabolism
  • Fluorouracil / chemistry
  • Fluorouracil / metabolism
  • Humans
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Workflow

Substances

  • Antimetabolites, Antineoplastic
  • Antiviral Agents
  • Pharmaceutical Preparations
  • Fluorouracil