geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Can the energy gap in the protein-ligand binding energy landscape be used as a descriptor in virtual ligand screening?


, : Can the energy gap in the protein-ligand binding energy landscape be used as a descriptor in virtual ligand screening?. Plos One 7(10): E46532-E46532

The ranking of scores of individual chemicals within a large screening library is a crucial step in virtual screening (VS) for drug discovery. Previous studies showed that the quality of protein-ligand recognition can be improved using spectrum properties and the shape of the binding energy landscape. Here, we investigate whether the energy gap, defined as the difference between the lowest energy pose generated by a docking experiment and the average energy of all other generated poses and inferred to be a measure of the binding energy landscape sharpness, can improve the separation power between true binders and decoys with respect to the use of the best docking score. We performed retrospective single- and multiple-receptor conformation VS experiments in a diverse benchmark of 40 domains from 38 therapeutically relevant protein targets. Also, we tested the performance of the energy gap on 36 protein targets from the Directory of Useful Decoys (DUD). The results indicate that the energy gap outperforms the best docking score in its ability to discriminate between true binders and decoys, and true binders tend to have larger energy gaps than decoys. Furthermore, we used the energy gap as a descriptor to measure the height of the native binding phase and obtained a significant increase in the success rate of near native binding pose identification when the ligand binding conformations within the boundaries of the native binding phase were considered. The performance of the energy gap was also evaluated on an independent test case of VS-identified PKR-like ER-localized eIF2α kinase (PERK) inhibitors. We found that the energy gap was superior to the best docking score in its ability to more highly rank active compounds from inactive ones. These results suggest that the energy gap of the protein-ligand binding energy landscape is a valuable descriptor for use in VS.

US$19.90

PMID: 23071584

DOI: 10.1371/journal.pone.0046532


Other references

Meyer, H., 1974: Significance of food chemists from the food industry for environmental protection. Deutsche Lebensmittel Rundschau: 70 (1) 24-27

Geri, C.; Buiatti, M.; Parenti, R., 1970: Preliminary data on RNases from tissues cultivated in vitro of two species of Nicotiana and of their tumorous hybrid. The optimum pH value for cultivation of the tissues varied little around 5.5 for the tumourous hybrid, though it ranged from 3.0 to 6.0 for different cultures of AT. langsdorffii and from 4.5, to 6.4 for N. glauca. At least three RNases were detec...

Medvedovskaia, T.P.; Shepelev, V.N., 1970: Functional condition of the visual and vestibular analyzers in workers exposed to small doses of ionizing radiation. Gigiena Truda i Professional'nye Zabolevaniia 14(9): 44-46

Baston, C.; Balzer, S., 2004: Development of hotel room supply. This paper discusses: the effect of urban change on the hotel industry; the push and pull effects of hotel supply and demand; the drivers of hotel demand; and the factors that drive long-term sustainability in the hotel industry today.

Palestro C.J.; Swyer A.J.; Solomon R.W.; Lee S.O.; Kim C.K.; Goldsmith S.J., 1990: Orthopedic implant sepsis combined indium 111 leukocyte technetium 99m sulfur colloid imaging. Journal of Nuclear Medicine 31(5 SUPPL): 712

Fricker, G.; Miller, D.S., 2004: Modulation of drug transporters at the blood-brain barrier. A major challenge in the management of diseases of the central nervous system is the limited penetration of drugs into the brain. The structures responsible are the capillaries of the brain, whose endothelial cells form the so-called blood-brain b...

Nawrocki, G.; Cieplak, M., 2014: Amino acids and proteins at ZnO-water interfaces in molecular dynamics simulations. We determine potentials of the mean force for interactions of amino acids with four common surfaces of ZnO in aqueous solutions. The method involves all-atom molecular dynamics simulations combined with the umbrella sampling technique. The profile...

Wulferink, M.; Dierkes, S.; Gleichmann, E., 2002: Cross-sensitization to haptens: Formation of common haptenic metabolites, T cell recognition of cryptic peptides, and true T cell cross-reactivity. To analyze T cell cross-reactivity to para-compounds, we established CD4(+) T cell hybridomas from mice immunized with adducts of self-globin and one of three different para-compounds: p-aminophenol, p-phenylenediamine, or Bandrowski's base....

Rota-Stabelli, O.; Kayal, E.; Gleeson, D.; Daub, J.; Boore, J.L.; Telford, M.J.; Pisani, D.; Blaxter, M.; Lavrov, D.V., 2010: Ecdysozoan mitogenomics: evidence for a common origin of the legged invertebrates, the Panarthropoda. Ecdysozoa is the recently recognized clade of molting animals that comprises the vast majority of extant animal species and the most important invertebrate model organisms--the fruit fly and the nematode worm. Evolutionary relationships within the...

Sumpsi, J.M., 1977: The delimitation of the Mediterranean agricultural area in Spain. This paper begins with a brief discussion of the problems of Mediterranean regions as regards agriculture in general and as regards membership of or competition with the EEC. The main body of the paper attempts a new delimitation of Mediterranean...