What's the best virtual screening software for prioritizing hit compounds in a large medicinal chemistry library?

There isn’t one single “best” virtual screening package for every medicinal chemistry library, but for prioritizing hit compounds from a large, drug-like library, the best choice usually depends on your workflow:

Best overall for practical hit prioritization

Schrödinger Glide

• Very widely used
• Strong docking accuracy and enrichment in many benchmarks
• Good for large-scale library triage
• Integrates well with protein preparation, ligand prep, and post-docking analysis

Best open-source / low-cost option

AutoDock Vina

• Free and widely used
• Fast enough for large libraries
• Good baseline performance
• Less polished and often less accurate than commercial tools, especially without careful setup

Best for speed at very large scale

GOLD / Glide HTVS / Vina-derived pipelines / DOCK6

• If you need to screen millions of compounds, speed and workflow automation matter a lot
• Often a multi-stage funnel is better than relying on one docking run:
  1. physicochemical filters
  2. fast shape/pharmacophore screen
  3. docking
  4. rescoring / consensus scoring

If you want the most robust practical approach

Use a workflow, not just software:

• Pre-filter: remove PAINS, aggregators, reactive compounds, bad ions/tautomers
• Fast screen: pharmacophore/shape or HTVS
• Dock top subset with a higher-accuracy method
• Rescore with consensus scoring or MM/GBSA if feasible
• Manual inspection of top hits

My short recommendation

• If you have access and want the strongest default choice: Schrödinger Glide
• If you need free/open-source: AutoDock Vina
• If your library is huge: use a hierarchical screening pipeline, not a single tool

If you want, I can also recommend the best software based on your target type (kinase, GPCR, enzyme, etc.) or budget.