Jonathan S. Mason

CURRENT PHYSICIAN KNOWLEDGE OF THE THERAPEUTIC USE EXEMPTIONS (TUE)

Jonathan S. Mason, Mark Troxler

PURPOSE: Only physicians are allowed to sign the Therapeutic Use Exemptions (TUE) of the prohibited lists (PL) in national and international sports organizations. Review of literature has reported the important role physicians play in the TUE process. These studies have involved different …

Identification of nanomolar adenosine A2A receptor ligands using reinforcement learning and structure-based drug design

Morgan C. Thomas, Pierre G. Matricon, Robert F. Gillespie, Maja Napiórkowska et autres

Abstract Generative chemical language models (CLMs) have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based drug design (SBDD) principles with CLMs to go from protein structure to novel small-molecule ligands, without a priori knowledge …

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Modern hit-finding with structure-guided de novo design: identification of novel nanomolar adenosine A2A receptor ligands using reinforcement learning

Morgan C. Thomas, Pierre G. Matricon, Robert F. Gillespie, Maja Napiórkowska et autres

Generative chemical language models have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based drug design (SBDD) principles with chemical language models to present a modern hit-finding workflow to go from protein structure to novel …

gb (code pays fourni par la source)

Modern hit-finding with structure-guided de novo design: identification of novel nanomolar A2A receptor ligands using reinforcement learning

Morgan C. Thomas, Pierre G. Matricon, Robert F. Gillespie, Maja Napiórkowska et autres

Generative chemical language models have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based design principles with chemical language models to present a modern hit-finding workflow to go from protein structure to novel small-molecule ligands, …

gb (code pays fourni par la source)

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Willem Jespers, Grégory Verdon, Jhonny Azuaje, María Majellaro et autres

Abstract We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations …

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X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A 2A Adenosine Receptor Antagonists

Willem Jespers, Grégory Verdon, Jhonny Azuaje, María Majellaro et autres

Abstract We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A 2A adenosine receptor (AR). Eight A 2A AR …

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Accurate Prediction of GPCR Ligand Binding Affinity with Free Energy Perturbation

Francesca Deflorian, Laura Pérez‐Benito, Eelke Bart Lenselink, Miles Congreve et autres

The computational prediction of relative binding free energies is a crucial goal for drug discovery, and G protein-coupled receptors (GPCRs) are arguably the most important drug target class. However, they present increased complexity to model compared to soluble globular proteins. Despite breakthroughs, …

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Impact of Recently Determined Crystallographic Structures of GPCRs on Drug Discovery

Francesca Deflorian, Jonathan S. Mason, Andrea Bortolato, Benjamin Gerald Tehan

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins. GPCRs are involved in a wide variety of cellular functions, serving as key players in cellular signaling. To aid the visualization of key properties of the ligand binding sites, GRID maps …

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X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Willem Jespers, Grégory Verdon, Jhonny Azuaje, María Majellaro et autres

Nowadays, rigorous free energy calculations are routinely considered in pharmaceutical design strategies. One typical sce- nario is the lead-optimization based on well-defined protein-ligand binding modes, inferred by pharmacological data in com- putational models and ultimately revealed by structural data. In this work, …

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X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Willem Jespers, Grégory Verdon, Jhonny Azuaje, María Majellaro et autres

Nowadays, rigorous free energy calculations are routinely considered in pharmaceutical design strategies. One typical sce- nario is the lead-optimization based on well-defined protein-ligand binding modes, inferred by pharmacological data in com- putational models and ultimately revealed by structural data. In this work, …

se (code pays fourni par la source)

Understanding Ligand Binding Selectivity in a Prototypical GPCR Family

Giulio Mattedi, Francesca Deflorian, Jonathan S. Mason, Chris de Graaf et autres

High Resolution Image Download MS PowerPoint Slide Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack …

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Analysis of tractable allosteric sites in G protein-coupled receptors

Amanda Wakefield, Jonathan S. Mason, Sándor Vajda, György Miklós Keserű

Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we …

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