Molecular docking using shape descriptors

Shoichet, Brian K.; Bodian, Dale L.; Kuntz, Irwin D.

doi:10.1002/jcc.540130311

Cited by 385 publications

(293 citation statements)

References 42 publications

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“…43 Up to 500 conformations of each docking molecule were sampled; the average number of conformations for each molecule was 345. For calculating orientations in the site, receptor and ligand "bins" were set to 0.5 Å and "overlap bins" were set to 0.25 Å, 37 with a distance tolerance for matching sphere-atom pairs of 1.25 Å. On average, 341 orientations were sampled for each conformation of each molecule.…”

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confidence: 99%

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

et al. 2002

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High-throughput screening (HTS) of compound libraries is used to discover novel leads for drug development. When a structure is available for the target, computer-based screening using molecular docking may also be considered. The two techniques have rarely been used together on the same target. The opportunity to do so presented itself in a project to discover novel inhibitors for the enzyme protein tyrosine phosphatase-1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for type II diabetes. A corporate library of approximately 400 000 compounds was screened using high-throughput experimental techniques for compounds that inhibited PTP1B. Concurrently, molecular docking was used to screen approximately 235 000 commercially available compounds against the X-ray crystallographic structure of PTP1B, and 365 high-scoring molecules were tested as inhibitors of the enzyme.Of approximately 400 000 molecules tested in the high-throughput experimental assay, 85 (0.021%) inhibited the enzyme with IC 50 values less than 100 µM; the most active had an IC 50 value of 4.2 µM. Of the 365 molecules suggested by molecular docking, 127 (34.8%) inhibited PTP1B with IC 50 values less than 100 µM; the most active of these had an IC 50 of 1.7 µM. Structure-based docking therefore enriched the hit rate by 1700-fold over random screening. The hits from both the high-throughput and docking screens were dissimilar from phosphotyrosine, the canonical substrate group for PTP1B; the two hit lists were also very different from each other. Surprisingly, the docking hits were judged to be more druglike than the HTS hits. The diversity of both hit lists and their dissimilarity from each other suggest that docking and HTS may be complementary techniques for lead discovery.

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confidence: 99%

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

et al. 2002

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“…Docking of potential inhibitors of GRK2 and cAPK was performed using the DOCK 3.5 software package [16][17][18][19] . Briefly, a molecular surface of the target site was created using the MS algorithm 27 .…”

Section: Docking Of Potential Inhibitors Of Grk2mentioning

confidence: 99%

“…Knowledge of the 3D structure of the enzyme can be useful in the design of potent and selective inhibitors. The docking of compounds in large chemical databases into a molecular model of a target protein using the DOCK software package developed by Kuntz and collegues [16][17][18][19] has proven valuable as a screening procedure, providing insight into ligand-receptor interactions and suggesting possible lead compounds 20 . However, the crystal structure of GRK2 has yet to be reported.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling of G-protein coupled receptor kinase 2: Docking and biochemical evaluation of inhibitors

et al. 2000

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G-protein coupled receptor kinase 2 (GRK2) regulates the activity of many receptors. Because potent inhibitors of GRK2 are thus far limited to polyanionic compounds like heparin, we searched for new inhibitors with the aid of a molecular model of GRK2. We used the available crystal structure of cAMP dependent protein kinase (cAPK) as a template to construct a 3D homology model of GRK2. Known cAPK and GRK2 inhibitors were docked into the active sites of GRK2 and cAPK using DOCK v3.5. H8 docked into the hydrophobic pocket of the adenosine 5'-triphosphate (ATP) binding site of cAPK, consistent with its known competitive cAPK inhibition relative to ATP. Similarly, 3 of 4 known GRK2 inhibitors docked into the ATP binding pocket of GRK2 with good scores. Screening the Fine Chemicals Directory (FCD, containing the 3D structures of 13,000 compounds) for docking into the active sites of GRK2 identified H8 and the known GRK2 inhibitor trifluoperazine as candidates. Whereas H8 indeed inhibited light-dependent phosphorylation of rhodopsin by GRK2, but with low potency, 3 additional FCD compounds with promising GRK2 scores failed to inhibit GRK2. This result demonstrates limitations of the GRK2 model in predicting activity among diverse chemical structures. Docking suramin, an inhibitor of protein kinase C (not present in FCD) yielded a good fit into the ATP binding site of GRK2 over cAPK. Suramin did inhibit GRK2 with IC50 32 μM (pA 2 6.39 for competitive inhibition of ATP). Suramin congeners with fewer sulfonic acid residues (NF062, NF503 [IC50 14 μM]) or representing half of the suramin molecule (NF520) also inhibited GRK2 as predicted by docking. In conclusion, suramin and analogues are lead compounds in the development of more potent and selective inhibitors of GRK2.

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“…The DOCK algorithm (Kuntz et al 1982;Desjarlais et al 1986;Shoichet et al 1992) attempts to generate geometrically feasible alignments of ligands within a receptor site of known structure based on a detailed matching of molecular surfaces. The volume of the binding site and that of potential ligands are first represented as a series of spheres which fit into their respective solvent accessible surfaces (Connolly, 1983).…”

Section: Shape Based Dockingmentioning

confidence: 99%