Therapeutically targeting guanylate cyclase‐C: computational modeling of plecanatide, a uroguanylin analog

Plecanatide is a recently developed guanylate cyclase‐C (GC‐C) agonist and the first uroguanylin analog designed to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS‐C). GC‐C receptors are found across the length of the intestines and are thought to play a key role in fluid regulation and electrolyte balance. Ligands of the GC‐C receptor include endogenous agonists, uroguanylin and guanylin, as well as diarrheagenic, Escherichia coli heat‐stable enterotoxins (ST). Plecanatide mimics uroguanylin in its 2 disulfide‐bond structure and in its ability to activate GC‐Cs in a pH‐dependent manner, a feature associated with the presence of acid‐sensing residues (Asp2 and Glu3). Linaclotide, a synthetic analog of STh (a 19 amino acid member of ST family), contains the enterotoxin's key structural elements, including the presence of three disulfide bonds. Linaclotide, like STh, activates GC‐Cs in a pH‐independent manner due to the absence of pH‐sensing residues. In this study, molecular dynamics simulations compared the stability of plecanatide and linaclotide to STh. Three‐dimensional structures of plecanatide at various protonation states (pH 2.0, 5.0, and 7.0) were simulated with GROMACS software. Deviations from ideal binding conformations were quantified using root mean square deviation values. Simulations of linaclotide revealed a rigid conformer most similar to STh. Plecanatide simulations retained the flexible, pH‐dependent structure of uroguanylin. The most active conformers of plecanatide were found at pH 5.0, which is the pH found in the proximal small intestine. GC‐C receptor activation in this region would stimulate intraluminal fluid secretion, potentially relieving symptoms associated with CIC and IBS‐C.