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Understanding Ligand Binding Selectivity in a Prototypical GPCR Family.

ABSTRACT: 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 of selectivity which results in unwanted side effects. The extensive structural similarity of adenosine receptors complicates the design of selective ligands. The problem of selective targeting is a general concern in GPCRs, and in this respect adenosine receptors are a prototypical example. Here we use enhanced sampling simulations to decipher the determinants of selectivity of ligands in A_2a and A₁ adenosine receptors. Our model shows how small differences in the binding pocket and in the water network around the ligand can be leveraged to achieve selectivity.

SUBMITTER: Mattedi G

PROVIDER: S-EPMC7007187 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Understanding Ligand Binding Selectivity in a Prototypical GPCR Family.

Mattedi Giulio G Deflorian Francesca F Mason Jonathan S JS de Graaf Chris C Gervasio Francesco L FL

Journal of chemical information and modeling 20190604 6

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 of selectivity which results in unwanted side effects. The extensive structural similarity of adenosine receptors complicates the design of selective ligands. The problem of selective targeting is a general concern in GPCRs, and in this respect adenosine receptors are a p ...[more]

PMID: 31125224

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