Phospholipase A2 (PLA2) enzymes are the upstream regulators of the eicosanoid pathway liberating free fatty acids including arachidonic acid (AA). The liberation of AA by PLA2 enzymes sets off a cascade of molecular events that involves downstream regulators such as cyclooxygenase (COX) and lipoxygenase (LOX) metabolites leading to inflammation (Nat. Rev. Immunol. 2015, 15, 511-523). Nonsteroidal anti-inflammatory drugs (NSAID) work by inhibiting COX and LOX which both rely on PLA2 enzymes to provide them with AA. That means PLA2 enzymes can potentially also be targeted to diminish inflammation at an earlier point in the process. Group IVA cytosolic PLA2 (cPLA2) is specific for AA and is mainly involved in inflammation (J. Am. Chem. Soc. 2018, 140, 3285-3291). Identifying inhibitors for cPLA2 is very challenging because it is a membrane-associated enzyme. The available crystal structure for this enzyme does not contain a co-crystallized ligand. Molecular docking was employed to generate enzyme-inhibitor interaction models by using a previously published cPLA2 inhibitor (J. Med. Chem. 2016, 59, 4403-4414). Molecular dynamics guided by hydrogen/deuterium exchange were employed to obtain five conformations of cPLA2 to virtually screen compound libraries. Forty compounds were selected based on the binding mode, theoretical binding score and frequency of top-ranked poses in the five conformations of cPLA2. These compounds were ordered and screened in vitro for inhibitory activity against cPLA2. The active compounds were also tested against calcium-independent and secreted PLA2 for selectivity. This study let to the identification of hit compounds that were evaluated in a cell-based assay. Lipidomics analysis showed that the hit compounds penetrate macrophages and reduce the production of inflammatory mediators by inhibiting cPLA2. Hit compounds will undergo lead optimization to improve inhibitory potency against cPLA2. The existing study demonstrated the importance of computer-aided drug design in identifying inhibitors for challenging biological targets.

Identifying inhibitors for lipolytic enzymes: A step towards the development of anti-inflammatory agents

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.