Pre-Conference Workshop Day

Monday, November 16 2020

Workshop A: Cryo-EM and its Applications for Structure-Based Drug Design

10:00 a.m. - 12:30 p.m.

Cryo-electron microscopy (cryo-EM) is the method for structure determination of biomolecules. In recent years, cryo-EM has revolutionized structural biology by providing unprecedented insights into structure of proteins not amenable to crystallization. The 2017 Nobel Prize in Chemistry was awarded for developing cryo-EM for the high–resolution structure determination of biomolecules in solution. In cryo-EM, the beam of high-energy electrons scatters at the specimen embedded in vitreous ice producing images on the detector. The images correspond to the 2-D projections of the vitrified macromolecules. These images are then used for the reconstruction of 3-D structures of the macromolecules using various mathematical algorithms. With recent advances of direct electron detectors, improvements of the microscope optics, and developments in image processing and structure calculation algorithms, it is now possible to obtain structures of macromolecular complexes with local resolution reaching less than 2 Å. These advances allow for the analysis of drug interactions with protein targets and show the strong potential of cryo-EM for structure-based drug design.

 

Key topics for this workshop will include:

  • Physical basis of cryo-EM
  • Workflows for sample preparation and optimization
  • Methods for microscope alignments and high-resolution data acquisition
  • Algorithms for high-resolution structure determination
  • Applications of cryo-EM to structure-based drug design
  • Challenges for cryo-EM in the process of drug discovery

Workshop Leader:

 

Arek Kulczyk
Assistant Professor of Biochemistry
Rutgers University

 

 

 

 

 

Workshop B: Fusion of Biophysics & Simulation in Drug Discovery

1:30 p.m. - 4:00 p.m.

Understanding the relationship between protein conformation and biological activity is a key cornerstone of drug discovery that is often misunderstood or ignored because of the lack of dynamic information generated in the drug discovery process. The generation and use of structural information have become a salient part of the drug optimization process which relies heavily on static crystallographic information as a representation of a protein active site.

However, biophysical techniques, such as protein and ligand detected NMR and hydrogen-deuterium exchange, are powerful approaches for understanding how ligand binding effects protein conformation and function. Molecular dynamics simulations have emerged as an important tool for modeling protein flexibility, at both the binding site-level and at the level of macroscopic conformational states.

This workshop will illustrate examples of using molecular dynamics simulation, in concert with biophysical results, to enhance drug discovery.

 

Key topics for this workshop will include:

  • Biophysical techniques implemented across the different stages of drug discovery
  • The evolution of computational simulation over the past 20 years in the context of impacting drug discovery
  • Enabling structure-based drug design by fusing different biophysical techniques biophysics and computational approaches
  • Case studies illustrating the impact from early target identification to lead discovery and optimization

Workshop Leaders:

Steve Swann
Senior Director of Medicinal Chemistry & Computational Design
Silicon Therapeutics


Mark Bures
Director of Modeling & Simulations
Silicon Therapeutics