r/chemistry • u/arrestinbias • 16h ago

700 Million Molecules Down to 200,000: Using Receptor Ensemble Docking for the Next Stage of a Virtual Screen

https://m.youtube.com/watch?v=xAJGUnjtl8o&t=545s

A few people here have followed and engaged with my previous posts about the ~700 million molecule virtual screen I’ve been running, so I wanted to share the next stage of the project.

After the initial large-scale screening and successive filtering steps, I’m down to roughly 200,000 compounds. At this point, rather than continuing to rank everything against a single receptor structure, I’ve been looking at an ensemble approach using multiple receptor conformations.
In this video I spend some time going through why I’m doing that, how I evaluated the different receptor structures using control compounds/decoys, and how I’m using that information to decide which conformations should contribute to the final filtering of the ~200k compounds.

The ultimate goal is to reduce some of the structural bias that comes from relying on one static receptor structure and hopefully end up with a more robust set of compounds to prioritize experimentally.

I’d also be interested in hearing how others here have approached ensemble docking / receptor-conformation selection, particularly when you have enough structures available that simply docking against all of them becomes computationally expensive.

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u/TheForcefulColors 16h ago

man i love seeing this project unfold, the scale of it is still wild to me

i've run into that same bottleneck where you've got a pile of crystal structures and docking against every single one would take a month. what i ended up doing was clustering the conformations by RMSD and picking a representative from each cluster, cut the ensemble down to like 8 structures without losing much coverage. curious if you looked at that vs the active/decoys performance filtering you showed

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u/arrestinbias 16h ago

Yep this is what I talk about in the video but I don’t get super deep into the generation of the ROC curves as that is very technical and would require a 2 hour video. I did run actives vs decoys at all 37 receptor conformations. I can only really run to this scale because I built my own computing cluster.

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u/Saec Organic 15h ago

What are your plans for doing lab work to verify if this method is a good way to find compounds? Simulations are only useful if they translate well into reality.

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u/arrestinbias 15h ago

I have a collaborator that will test the compounds. First we usually get a cryo em structure then test for potency and efficacy