A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Juliana, Christine; Chai, Jinghua; Arroyo, Pablo; Rico-Bautista, Elizabeth; Betz, Stephen F.; León, Diva D. De

doi:10.1016/j.jbc.2023.104816

Cited by 2 publications

(2 citation statements)

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“…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. 7,8 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. 9−12 However, the experimental complex structures that are available are not bound to the ligand chemotypes represented in the various series that we investigate here.…”

Section: Introductionmentioning

confidence: 99%

“…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?…”

Section: Introductionmentioning

confidence: 99%

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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

Coskun,

Lihan,

Rodrigues

et al. 2023

J. Chem. Theory Comput.

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Free energy perturbation (FEP) remains an indispensable method for computationally assaying prospective compounds in advance of synthesis. However, before FEP can be deployed prospectively, it must demonstrate retrospective recapitulation of known experimental data where the subtle details of the atomic ligand−receptor model are consequential. An open question is whether AlphaFold models can serve as useful initial models for FEP in the regime where there exists a congeneric series of known chemical matter but where no experimental structures are available either of the target or of close homologues. As AlphaFold structures are provided without a bound ligand, we employ induced fit docking to refine the AlphaFold models in the presence of one or more congeneric ligands. In this work, we first validate the performance of our latest induced fit docking technology, IFD-MD, on a retrospective set of public experimental GPCR structures with 95% of cross-docks producing a pose with a ligand RMSD ≤ 2.5 Å in the top two predictions. We then apply IFD-MD and FEP on AlphaFold models of the somatostatin receptor family of GPCRs. We use AlphaFold models produced prior to the availability of any experimental structure from this family. We arrive at FEP-validated models for SSTR2, SSTR4, and SSTR5, with RMSE around 1 kcal/mol, and explore the challenges of model validation under scenarios of limited ligand data, ample ligand data, and categorical data.

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Section: Introductionmentioning

confidence: 99%