Another in our series of seminars.
Title: Charting therapeutically relevant protein conformational space with adaptive MD
Registration: cost - £0; deadline - 31 May 2021, maximum number of participants - 500;
Speaker: Silvia Lovera, UCB BioPharma
Abstract:
GPCRs play a pivotal role in transmitting signals at the cellular level and structural insights can be exploited to support structure-based drug discovery endeavors. Despite advances in GPCR crystallography, it remains challenging to obtain crystal structures particularly of active states. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Nevertheless, the search for physiologically relevant conformations, allosteric pockets and ligand binding events using classical MD simulations is still impractical.
The work I will present shows how by applying adaptive MD it is possible to computationally access, in a rigorous and timely manner, key functional states of a GPCR without a priori structural information of the active state [1]. Moreover, I will show that this cutting-edge MD methodology can help elucidating GPCRs regulatory mechanisms and opening avenues for the study of ligands binding to elusive yet pharmacologically important GPCR states, providing key insights into ligands mode of action [2].
[1] S. Lovera, A. Cuzzolin, S. Kelm, G. De Fabritiis, Z. A. Sands. Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots. Sci Rep 9, 14199 (2019)
[2] S. Lovera, E.J.B. Landin, G. De Fabritiis, S. Kelm, J. Mercier, D. McMillan, R.B. Sessions, R.J. Taylor, Z. A. Sands, L. Joedicke, M.P. Crump. The Aminotriazole Antagonist Cmpd-1 Stabilises a Distinct Inactive State of the Adenosine 2A Receptor. Angewandte Chemie Int. Ed. 58, 1-6 (2019)
