Structure-based drug design for protein arginine deiminase Type IV (PAD4) receptor: Chemoinformatics approach

Rheumatoid Arthritis (RA) is the second most common type of arthritis with symptoms first appearing in patients between 40 and 60 years of age. The number of older persons is projected to double to 1.5 billion in 2050, globally. Peptidylarginine deiminase Type 4 (PAD4), which catalyzes the conversion of peptidyl-arginine to peptidyl-citrulline, is widely believed to play a causative role in RA disease. Nonsteroidal anti-inflammatories (NSAIDs) and corticosteroids encompass a large group of clinically effective compounds whose mode of action is well established, these compounds relieve pain and reduce inflammation by preventing prostaglandin synthesis through inhibition of cyclooxygenase 2 and the production of arachidonic acid, respectively. We developed a computational protocol/pipeline, using virtual screening approaches to search for new chemical agents (NCA), capable of inhibiting the action of PAD4, in potential, in view of the treatment of RA. Our results allowed the selection of structures with suitable indices of pharmacokinetic properties and estimated low toxicological, in potential, important evidence for selection of more promising molecular candidates against the studied disease. Molecules ZINC20452582 and ZINC67673633 presented better results, as well as the drug-receptor interactions were similar to those observed between the crystallographic compound (GSK147) here used. They presented excellent results for predictions of metabolites, and they can be indicated as promising molecules, resulting from virtual screening approaches, as new PAD4 receptor inhibitors with activity against RA, in potential.