This protocol is tested using protein tyrosine phosphatase 1B (PTP1B) as a benchmark system. PTP1B is a negative regulator of insulin signalling . Inhibition of PTP1B has been proposed as a therapeutic strategy for type II diabetes treatments . The protein enzymatic activity is regulated by the conformations adopted by the WPD loop that sits above the active site. The WPD loop adopts two major conformations -open and closed (Figure ). The closed conformation is catalytically active, as it positions the catalytic residues in range of the substrate . The closing and opening of the loop occurs on multimicrosecond timescales . The charged and highly conserved nature of the PTP1B active site has made it a challenging to develop orally bioavailable ligands that act as competitive inhibitors. Therefore allosteric inhibition of PTP1B enzymatic activity is an attractive drug design strategy .