Lipidomics-based assays coupled with computational approaches can identify novel phospholipase A2 inhibitors

Varnavas D Mouchlis; Carol Mu; Renee Hammons; Edward A Dennis

doi:10.1016/j.jbior.2020.100719

Lipidomics-based assays coupled with computational approaches can identify novel phospholipase A₂ inhibitors

Adv Biol Regul. 2020 May:76:100719. doi: 10.1016/j.jbior.2020.100719. Epub 2020 Mar 10.

Authors

Varnavas D Mouchlis¹, Carol Mu², Renee Hammons², Edward A Dennis³

Affiliations

¹ Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093-0601, USA. Electronic address: vmouchlis@gmail.com.
² Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093-0601, USA.
³ Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093-0601, USA. Electronic address: edennis@ucsd.edu.

Abstract

Phospholipase A₂ (PLA₂) enzymes play a major role in many diseases including the inflammatory cascade and specific potent small molecule inhibitors could be useful in studying their physiological role as well as for the development of drugs. In order to discover novel small molecule inhibitor platforms for members of the PLA₂ superfamily of enzymes, we have applied computational approaches to determine the binding mode of potent inhibitors specific for particular PLA₂s to the screening of chemical libraries. This has including the U.S. National Institutes of Health (NIH) National Cancer Institute (NCI) Diversity Set V and the ChemBridge commercial compound libraries. We have then subjected identified inhibitor structures to recently developed lipidomics based screening assays to determine the X_I(50) and specificity of the identified compounds for specific PLA₂s. Herein we review this approach and report the identity of initial hits for both the Group IVA cytosolic PLA₂ and the Group VIA calcium-independent PLA₂ that are worthy of further structural modification to develop novel platforms for inhibitor development.

Keywords: Dose-response inhibition; Enzymatic assays; Hit compounds; Phospholipase A(2); Virtual screening.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Binding Sites
Fatty Acids, Nonesterified / analysis
High-Throughput Screening Assays*
Lipidomics / methods*
Lysophospholipids / analysis
Molecular Docking Simulation
Molecular Dynamics Simulation
Phospholipase A2 Inhibitors / chemistry*
Phospholipases A2 / chemistry*
Phospholipases A2 / classification
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Small Molecule Libraries / chemistry*
Substrate Specificity
User-Computer Interface

Substances

Fatty Acids, Nonesterified
Lysophospholipids
Phospholipase A2 Inhibitors
Small Molecule Libraries
Phospholipases A2

Abstract

Publication types

MeSH terms

Substances

Grants and funding