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K-State Today Student Edition

March 6, 2018

March 7: Yinglong Miao presents Biochemistry and Molecular Biophysics Seminar

By Biochemistry and Molecular Biophysics

Yinglong Miao, assistant professor of molecular biosciences and assistant professor in the Center for Computational Biology at the University of Kansas, will present "Accelerated Computer Simulations and Drug Discovery of G-Protein-Coupled Receptors" at 4 p.m. Wednesday, March 7, in 120 Ackert Hall as part of the Biochemistry and Molecular Biophysics Seminar series.

Presentation abstract: G-protein-coupled receptors, or GPCRs, represent primary targets of about one-third of currently marketed drugs. However, GPCR drug discovery has suffered from major challenges, including the inherent flexibility of the receptors and the toxicity of agonist and antagonist drugs that are designed to bind the conserved "orthosteric" site. Here, we have performed all-atom computer simulations using a robust Gaussian accelerated molecular dynamics (GaMD)[1] method to investigate mechanisms of ligand binding and activation of the muscarinic GPCRs. GaMD simulations captured spontaneous binding of endogenous agonist acetylcholine to the M3 muscarinic receptor. Both dissociation and binding of an orthosteric ligand were observed in a single all-atom simulation of the M2 muscarinic receptor. Further GaMD simulations revealed distinct structural flexibility and free energy profiles that depict graded activation of the M2 receptor[2]. In addition, we have implemented a unique structure-based approach to design allosteric modulators as selective drug leads of the M2 receptor. Through iterative molecular docking and experimental testing, half of our 38 computationally selected lead compounds were validated as effective allosteric modulators of the M2 receptor. Our method successfully identified both positive and negative allosteric modulators of the M2 receptor with unprecedented chemical diversity and outstanding potential for further structure-activity relationship studies[3]. Finally, I will talk about our recent simulation studies to elucidate binding modes of allosteric drug leads in the adenosine A1 receptor, which will provide valuable insights for future structure-based computer-aided drug design efforts.

References:
1. Miao, Y. and J.A. McCammon, "Gaussian Accelerated Molecular Dynamics: Theory, Implementation and Applications". Annual Reports in Computational Chemistry, 2017. 13: p. 231-278.
2. Miao, Y. and J.A. McCammon, "Graded activation and free energy landscapes of a muscarinic G-protein–coupled receptor". Proc Natl Acad Sci U S A, 2016. 113(43): p. 12162–12167.
3. Miao, Y., et al., "Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor". Proc Natl Acad Sci U S A, 2016. 113(38): p. E5675–E5684.

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