This Structure Based Computational Methods in Drug Design Workshop at SSRL introduces the core concepts of computational ("in-silico") drug discovery, walking participants through the complete workflow, from the starting protein receptor and ligand structures through docking. Click here to register for the workshop.

Our primary focus will be structure-based drug design, with additional discussion of complementary computational approaches. We will address the key practical challenges at each stage: obtaining a usable receptor structure (from the PDB, or via homology modeling when no experimental structure is available), preparing it for calculations, accessing and screening the large ligand libraries used in virtual screening, running docking calculations, and interpreting the results. Beyond docking itself, we will discuss why a single static structure is often insufficient, and how conformational sampling can improve results. The aim is a practical, concept-first overview that remains broadly useful regardless of the specific software a researcher ultimately adopts.

Specifically, we plan to demonstrate the following:

Structure-based drug design

• Receptor preparation — downloading a structure from the PDB, adding hydrogens, correcting residue and geometry problems, and performing energy minimization
• Homology modeling — building a model from the closest available structure when no experimental one exists
• Accessing ligand libraries — where to find and how to download screening databases, the file formats involved, and how to prepare a library for docking
• Docking — running docking calculations (blind, targeted, and pharmacophore-based), interpreting the resulting scores, and visualizing protein–ligand interactions
• Conformational sampling — moving beyond traditional single-structure docking to ensemble docking, and the methods used to generate protein conformations, including a brief look at molecular dynamics for producing multiple conformations for more reliable docking

Fragment-based drug design
• Fragment approaches — docking small fragments, then linking, merging, or replacing them to grow larger, higher-affinity molecules

Ligand-based drug design
• QSAR — using known actives and their chemical properties to identify new candidates when the target structure is unknown

These concepts will be illustrated primarily using MOE as an all-in-one teaching tool. In the last third of the workshop, we will also demonstrate our new automated open-source fragment screening pipeline at SSRL incorporating tools such as AutoDock Vina, DiffDock, BRIX, Fragmenstein, ProLIF, and Amber which any user with an account on our machines can run end-to-end. A scaled-down version of the pipeline will be prepared for the workshop attendees to test.

We recommend extending your stay to attend the 83rd Pittsburgh Diffraction Conference, which also takes place at SLAC and begins immediately after the workshop. The conference includes informative sessions, including one on structure-based drug development. For more information visit the conference website which also has information on local accommodations and travel.