Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D

Kick, Ellen K.; Roe, Diana C.; Skillman, A. Geoffrey; Liu, Guangcheng; Ewing, Todd; Sun, Yaxiong; Kuntz, Irwin D.; Ellman, Jonathan A.

doi:10.1016/s1074-5521(97)90073-9

Cited by 165 publications

(111 citation statements)

References 31 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…If we imagine that on the order of 0.1% of a diverse database might have activity for a given target, then to have more than a handful of hits in the top 0.5% of a database of the size used here would require an enrichment factor of around 20-fold, which is typically considered a good improvement over random selection. 32 With an enrichment of 20-fold, one could expect 10 hits in the top 500 compounds, such that there is a 2% chance that a given compound is active. In an academic lab, one might reasonably test 20 to 50 compounds; even with a 20-fold enrichment, the chance that all 20 compounds are inactive is still 67%; for 50 compounds tested, the chance that all are inactive is 36%.…”

Section: Discussionmentioning

confidence: 99%

Information Decay in Molecular Docking Screens against Holo, Apo, and Modeled Conformations of Enzymes

2003

View full text Add to dashboard Cite

Molecular docking uses the three-dimensional structure of a receptor to screen a small molecule database for potential ligands. The dependence of docking screens on the conformation of the binding site remains an open question. To evaluate the information loss that occurs as the active site conformation becomes less defined, a small molecule database was docked against the holo (ligand bound), apo, and homology modeled structures of 10 different enzyme binding sites. The holo and apo representations were crystallographic structures taken from the Protein Data Bank (PDB), and the homology-modeled structures were taken from the publicly available resource ModBase. The database docked was the MDL Drug Data Report (MDDR), a functionally annotated database of 95 000 small molecules that contained at least 35 ligands for each of the 10 systems. In all sites, at least 99% of the molecules in the MDDR were treated as nonbinding decoys. For each system, the holo, apo, and modeled structures were used to screen the MDDR, and the ability of each structure to enrich the known ligands for that system over random selection was evaluated. The best overall enrichment was produced by the holo structure in seven systems, the apo structure in two systems, and the modeled structure in one system. These results suggest that the performance of the docking calculation is affected by the particular representation of the receptor used in the screen, and that the holo structure is the one most likely to yield the best discrimination between known ligands and decoy molecules, but important exceptions to this rule also emerge from this study. Although each of the holo, apo, and modeled conformations led to enrichment of known ligands in all systems, the enrichment did not always rise to a level judged to be sufficient to justify the effort of a docking screen. Using a 20-fold enrichment of known ligands over random selection as a rough guideline for what might be enough to justify a docking screen, the holo conformation of the enzyme met this criterion in eight of 10 sites, whereas the apo conformation met this criterion in only two sites and the modeled conformation in three.

show abstract

Section: Discussionmentioning

confidence: 99%

Information Decay in Molecular Docking Screens against Holo, Apo, and Modeled Conformations of Enzymes

2003

View full text Add to dashboard Cite

show abstract

“…Such studies are now appearing in the literature (Brown andMartin, 1996, 1997;Matter, 1997;Patterson et al, 1996) but only that by Snarey et al (1998) has provided a detailed analysis of some of the dissimilarity-based selection methods considered in this paper. More importantly, the full value of methods for analysis molecular diversity will only be obtained when they are linked to other, existing approaches to computer-aided molecular design, such as ligand docking, pharmacophore mapping and quantitative structure-activity relationships (Martin and Willett, 1998): the merits of such linked approaches are well illustrated by very recent work on the docking of combinatorial libraries (Jones et al, 1999;Kick et al, 1997), and we can expect many further such reports in the next few years.…”

Section: Discussionmentioning

confidence: 99%

Dissimilarity-Based Algorithms for Selecting Structurally Diverse Sets of Compounds

Willett

1999

Journal of Computational Biology

View full text Add to dashboard Cite

“…Dimethylenastron was docked onto the coordinates obtained from the crystal structure of Eg5 [18] , using standard DOCK methodology [19] . The lowest-energy Eg5/dimethylenastron interaction model was presented.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…Dimethylenastron was docked onto the coordinates obtained from the crystal structure of Eg5 [18] , using standard DOCK methodology [19] , and the lowest-energy Eg5/ dimethylenastron interaction model was presented ( Figure 5A). Detailed analysis revealed that dimethylenastron binds to the motor domain of Eg5 in a pocket close to the ATP/ADP binding pocket on Eg5; there exist a loop (E116-R119) and an α-helix (G110-F113) between the two binding pockets ( Figure 5B).…”

Section: Dimethylenastron Allosterically Inhibits the Motor Domain Atmentioning

confidence: 99%

Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5

et al. 2011

View full text Add to dashboard Cite

Aim:The mitotic kinesin Eg5 plays a critical role in bipolar spindle assembly, and its inhibitors have shown impressive anticancer activity in preclinical studies. This study was undertaken to investigate the effect of dimethylenastron, a specific inhibitor of Eg5, on the migration and invasion of pancreatic cancer cells. Methods: Human pancreatic cancer cell lines PANC1, EPP85, BxPC3, CFPAC1, and AsPAC1 were used. Eg5 expression was examined using immunofluorescence microscopy. Cell migration and invasion were analyzed with wound healing and transwell assays. Cell proliferation was examined using sulforhodamine B and MTT assays. The binding of dimethylenastron to Eg5 was analyzed with a molecular modeling study, and the ADP release rate was examined with the MANT-ADP reagent. Results: Eg5 expression was 9-16-fold up-regulated in the 5 pancreatic cancer cell lines. Treatment of PANC1 pancreatic cancer cells with dimethylenastron (3 and 10 μmol/L) for 24 h suppressed the migratory ability of the cancer cells in a concentration-dependent manner. The invasion ability of the cancer cells was also reduced by the treatment. However, treatment of PANC1 cells with dimethylenastron (3 and 10 μmol/L) for 24 h had no detectable effect on their proliferation, which was inhibited when the cancer cells were treated with the drug for 72 h. Molecular modeling study showed that dimethylenastron could allosterically inhibit the motor domain ATPase of Eg5 by decreasing the rate of ADP release. Conclusion: Dimethylenastron inhibits the migration and invasion of PANC1 pancreatic cancer cells, independent of suppressing the cell proliferation. The findings provide a novel insight into the mechanisms of targeting Eg5 for pancreatic cancer chemotherapy.

show abstract

Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D

Cited by 165 publications

References 31 publications

Information Decay in Molecular Docking Screens against Holo, Apo, and Modeled Conformations of Enzymes

Information Decay in Molecular Docking Screens against Holo, Apo, and Modeled Conformations of Enzymes

Dissimilarity-Based Algorithms for Selecting Structurally Diverse Sets of Compounds

Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5

Contact Info

Product

Resources

About