Abstract
The pleiotropic role of human secretin (hSCT) validates its potential use as a therapeutic agent. Nevertheless, the structure of secretin in complex with its receptor is necessary to develop a suitable therapeutic agent. Therefore, in an effort to design a three-dimensional virtual homology model and identify a peptide agonist and/or antagonist for the human secretin receptor (hSR), the significance of the primary sequence of secretin peptides in allosteric binding and activation was elucidated using virtual docking, FRET competitive binding and assessment of the cAMP response. Secretin analogs containing various N- or C-terminal modifications were prepared based on previous findings of the role of these domains in receptor binding and activation. These analogs exhibited very low or no binding affinity in a virtual model, and were found to neither exhibit in vitro binding nor agonistic or antagonistic properties. A parallel analysis of the analogs in the virtual model and in vitro studies revealed instability of these peptide analogs to bind and activate the receptor.
Highlights
GPCRs are one of the largest receptor families [1]; these receptors share features in their molecular structure and signaling mechanisms and are regulated by a wide range of ligands such as hormones, peptides, neurotransmitters, chemokines, etc
SAR Studies of Secretin Analogs for the Human Secretin Receptor used as therapeutic agents [3]
Based on this information new molecules were designed in this study with modifications in the Nt region, whereas secretin from various non-mammalian vertebrates that contain variations in the Ct region were used as Ct-modified analogs to assess their effect on the human secretin receptor
Summary
GPCRs are one of the largest receptor families [1]; these receptors share features in their molecular structure and signaling mechanisms and are regulated by a wide range of ligands such as hormones, peptides, neurotransmitters, chemokines, etc. The extracellular N-terminal (Nt) region of the ligand is involved in secondary binding with the extracellular loop region and is responsible for downstream signaling [22,23,24] Based on this information new molecules were designed in this study with modifications in the Nt region, whereas secretin from various non-mammalian vertebrates that contain variations in the Ct region were used as Ct-modified analogs to assess their effect on the human secretin receptor (hSR). In the absence of an experimentally determined structure for hSR, a homology-modeled 3D receptor structure was developed to provide additional details on the receptor-ligand interaction These secretin analogs were studied in parallel with virtual docking, in vitro binding and functional assays to investigate their interaction with the hSR
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