Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics

ACS Pharmacol. Transl. Sci.

Barkan

Preti

et al. 2021

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Despite being amongst the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A 1 R) was determined in the active, G i protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A 1 R. Our results identify new residues involved in the association and dissociation pathway, suggest the binding mode of N6cyclopentyladenosine (CPA) related ligands, and highlight the dramatic effect that chemical modifications can have on the overall binding mechanism.

Section: Methodsmentioning

confidence: 99%

Section: Generation Of Mutantmentioning

confidence: 99%

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

ACS Pharmacol. Transl. Sci.

Barkan

Preti

et al. 2021

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“…In the first SuMD implementation ( Sabbadin and Moro, 2014 ; Cuzzolin et al, 2016 ), sampling is gained without the introduction of any energetic bias, by applying a tabu–like algorithm to monitor the distance between the centers of mass (or the geometrical centers) of the ligand and the predicted binding site or the receptor. However, the supervision of a second metric of the system can be considered ( Atanasio et al, 2020 ). A series of short unbiased MD simulations are performed, and, after each simulation, the distances (collected at regular time intervals) are fitted to a linear function.…”

Section: Methodsmentioning

confidence: 99%

Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Atanasio

Rujan

et al. 2021

Front. Mol. Biosci.

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Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

“…The supervised molecular dynamics (SuMD) is an adaptive sampling method for speeding up the simulation of binding [ 37 , 39 ] and unbinding processes [ 38 , 60 ]. Sampling is gained without the introduction of any energetic bias, by applying a tabu–like algorithm to monitor the distance between the centers of mass (or the geometrical centers) of the ligand and the predicted binding site or the receptor.…”

Section: Methodsmentioning

confidence: 99%

“…Sampling is gained without the introduction of any energetic bias, by applying a tabu–like algorithm to monitor the distance between the centers of mass (or the geometrical centers) of the ligand and the predicted binding site or the receptor. However, the supervision of a second metric of the system can be considered [ 60 ]. A series of short unbiased MD simulations are performed, and after each simulation, the distances (collected at regular time intervals) are fitted to a linear function.…”

Section: Methodsmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Prischi

Reynolds

2020

J Comput Aided Mol Des

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The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.