Characterizing clinically relevant natural variants of GPCRs using computational approaches
| Autor: | Manali Joshi, Krushna Sonar, Durba Sengupta |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetics education.field_of_study 030102 biochemistry & molecular biology Adrenergic receptor Population Single-nucleotide polymorphism Biology 03 medical and health sciences Disease susceptibility 030104 developmental biology Docking (molecular) Drug response education Receptor G protein-coupled receptor |
| Popis: | G protein-coupled receptors (GPCRs) are an important class of drug targets owing to their physiological role. A large number of clinically relevant single nucleotide polymorphisms (SNPs) have been observed in GPCRs that are linked to disease susceptibility and adverse drug response. It is therefore important to characterize the variants in order to improve GPCR therapeutics. Here, we discuss computational methods coupling molecular dynamics simulations with docking and free energy calculations to characterize the functional differences in GPCR variants. The hallmark of this approach is the explicit incorporation of receptor and membrane dynamics that allows us to analyze short- and long-range effects in the variant receptors. We use the SNPs reported in β 2 -adrenergic receptor (β 2 AR) as a test case and highlight the recent successes in analyzing structural and dynamic differences in a series of population variants. The computational approach we discuss here has a twofold benefit: it helps to unravel the molecular mechanisms underlying hypo- or hyperfunctionality of variant receptors as well as prioritizing novel variants that must be experimentally tested. |
| Databáze: | OpenAIRE |
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