Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine

Abstract

Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.

Using AlphaFold and Experimental Structures for the Prediction of the Structure and Binding Affinities of GPCR Complexes via Induced Fit Docking and Free Energy Perturbation

“…To illustrate the application of the IFD-MD/FEP-based approach to GPCR targets of current pharmaceutical interest, we chose in the present paper to work on the SSTR family of GPCRs. These proteins are currently being investigated as drug targets for a variety of disease indications, and a number of ligand series which bind tightly to the receptor have been published for each of the isoforms. , Furthermore, the situation with regard to SSTR experimental receptor structures is highly dynamic with new structures being released for SSTR4 and SSTR2 over the past months. − However, the experimental complex structures that are available are not bound to the ligand chemotypes represented in the various series that we investigate here. Therefore, the situation corresponds precisely to the question posed above: can IFD-MD, in conjunction with FEP, be used to identify the binding mode of the series (or multiple binding modes if that is the case) and can FEP achieve a good correlation with the experimental binding data for the series across a wide range of congeneric ligands?…”

Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

“…In the last year, different structures of SSTR2 in multiple conformational states have been published. ,,,,, Noteworthy, most of these structures are in complex with agonist ligands, which is often somatostatin or its analogous, like the octa-peptide octreotide. Both experimental and computational studies explored the conformational features of SSTR2 that are common to those of other class A GPCRs, and the key elements characterizing the binding with different types of ligands (see Figure S1 for an overview of the three-dimensional structure of SSTR2 and its main domains) .…”

The preparation of anti‐fouling dual‐layer composite membrane with embedding graphene oxide

“…10,11 Mahmoudi et al 12 reviewed that these problems can be solved by blending, coating, and grafting modification. Other materials, such as TiO 2 , 13 zeolite nanoparticles, carbon nanotubes (CNTs), 14,15 metal-organic coordination, 16 and graphene oxide (GO), 17 are incorporated into the membrane to increase the hydrophilicity and antibacterial properties to achieve high permeability and anti-fouling property. [18][19][20] Liu et al 21 found that higher water and protein solution fluxes could be obtained by blending; the water flux recovery ratio was also relatively higher.…”