Comparing virtual screening with high-throughput screening. High-throughput
screening (HTS) is the dominant method to identify novel leads for drug development. When the three-dimensional structure of the target is
available, virtual screening by molecular docking may also be used. How do the leads discovered by these methods compare? What sorts of hit rates
may be obtained from each method? We began to consider these questions in a recent project to identify novel inhibitors of the enzyme PTP1B, a
diabetes target. Using the Northwestern University version of DOCK, we virtually screened 165,000 molecules against the atomic resolution structure
of PTP1B; concurrently, our collaborators at Pharmacia experimentally screened an in-house library of 400,000 molecules against the same enzyme.
Surprisingly, the hits obtained from molecular docking were at least as drug-like as the hits from HTS. The hits from each technique were also quite
different from each other, despite structural similarity in the initial databases. Finally, the hit rate (when a hit is defined as a compound with an
IC50 < 100 μM) from molecular docking was 34.8%, and that from HTS was 0.021%, suggesting that molecular docking may be competitive
with HTS as a discovery method (Doman et al., Journal of Medicinal Chemistry, 2002).
| Technique |
Compounds
Tested |
Hits with
IC50 < 100 μM |
Hits with
IC50 < 10 μM |
Hit Rate |
| HTS |
400,000 |
85 |
6 |
0.021% |
| Docking |
365 |
127 |
21 |
34.8% |
Recent publications: - Atreya CE, Johnson EF, Irwin JJ, Dow A, Massimine KM, Coppens I, Stempliuk V, Beverley S, Joiner KA, Shoichet BK, Anderson KS. A molecular docking strategy identifies eosin B as a non-active Site Inhibitor of protozoal bifunctional thymidylate synthase-dihydrofolate reductase. J Biol Chem 278 (16), 14092-100 (2003). [Pubmed | DOI | Faculty of 1000 | Download PDF]
- Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, Stallings WC, Connolly DT, Shoichet BK. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem 45 (11), 2213-21 (2002). [Pubmed | DOI | NRDD Highlight | Faculty of 1000 | Download PDF]
- Powers RA, Morandi F, Shoichet BK. Structure-based discovery of a novel, non-covalent inhibitor of AmpC ß-lactamase. Structure 10 (7), 1013-23 (2002). [Pubmed | DOI | PDB 1L2S | Download PDF]
- Tondi D, Powers RA, Caselli E, Negri M, Blazquez J, Costi MP, Shoichet BK. Structure-based design and in-parallel synthesis of inhibitors of AmpC ß-lactamases. Chem Biol 8 (6), 593-611 (2001). [Pubmed | DOI | PDB 1GA9]
- Tondi D, Slomczynska U, Costi MP, Watterson DM, Ghelli S, Shoichet BK. Structure-based discovery and in-parallel optimization of novel competitive inhibitors of thymidylate synthase. Chem Biol 6 (5), 319-31 (1999). [Pubmed | DOI]
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