Abstract
Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of “one–disease, one–target, one–drug”. The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermore, single-target inhibitors are often susceptible to drug resistance and are ineffective for complex diseases such as cancers. Therefore, a new strategy is required for enriching the hit rate and identifying multitarget inhibitors. To address these issues, we propose the pathway-based screening strategy (called PathSiMMap) to derive binding mechanisms for increasing the hit rate and discovering multitarget inhibitors using site-moiety maps. This strategy simultaneously screens multiple target proteins in the same pathway; these proteins bind intermediates with common substructures. These proteins possess similar conserved binding environments (pathway anchors) when the product of one protein is the substrate of the next protein in the pathway despite their low sequence identity and structure similarity. We successfully discovered two multitarget inhibitors with IC50 of <10 µM for shikimate dehydrogenase and shikimate kinase in the shikimate pathway of Helicobacter pylori. Furthermore, we found two selective inhibitors (IC50 of <10 µM) for shikimate dehydrogenase using the specific anchors derived by our method. Our experimental results reveal that this strategy can enhance the hit rates and the pathway anchors are highly conserved and important for biological functions. We believe that our strategy provides a great value for elucidating protein binding mechanisms and discovering multitarget inhibitors.
Highlights
The concept of ‘‘one–disease, one–target, one–drug’’ has dominated drug development strategy for decades [1,2]
These inhibitors often lose potency owing to mutations in the protein binding sites and are ineffective for complex diseases
Compounds that bind these conserved binding environments are often multitarget inhibitors. We applied this strategy to the shikimate pathway of Helicobacter pylori, and discovered two multitarget inhibitors (IC50,10 mM) for shikimate dehydrogenase and shikimate kinase
Summary
The concept of ‘‘one–disease, one–target, one–drug’’ has dominated drug development strategy for decades [1,2] Based on this strategy, many virtual screening methods have been developed and applied successfully for identifying specific inhibitors of a single target [3,4,5]. The proteins in a metabolic pathway contain conserved binding environments where the product of one enzyme is the substrate of the enzyme in a series of catalytic reactions Using this property, it is possible to design a multitarget inhibitor to simultaneously inhibit multiple proteins in a disease pathway to increase the therapeutic effectiveness against the disease. A new strategy for extracting conserved binding environments from these proteins is needed for the discovery of multitarget inhibitors To address these issues, we propose a new strategy, called pathway-based screening by using pathway site-moiety maps
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