Analysis of subpocket selectivity and identification of potent selective inhibitors for matriptase and matriptase-2.
We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes.
Departments of Biochemistry and ‡Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada.
Dominic
D
Duchêne
Eloïc
E
Colombo
Antoine
A
Désilets
Pierre-Luc
PL
Boudreault
Richard
R
Leduc
Eric
E
Marsault
Rafael
R
Najmanovich
D020134:Catalytic Domain; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase; C467801:matriptase 2