The similarity between two microenvironments was determined using a Tanimoto-like score that identified the shared bits between two feature vectors.The pocket microenvironments between two sites were sequentially compared combinatorially to maximize the total matching scores.
The similarity between two microenvironments was determined using a Tanimoto-like score that identified the shared bits between two feature vectors.The pocket microenvironments between two sites were sequentially compared combinatorially to maximize the total matching scores.Tags: Racism In To Kill A Mockingbird Essay250 Word Essay On What Is Your Favorite Food ByBest Collections Of EssaysResearch Proposal GuidelinesCase Study EssayPersonal Statement Psychology Masters
One of the most widely used microtubule-stabilizing drugs is paclitaxel (Taxol, Bristol-Myers Squibb), a member of a class of diterpenes identified from the Pacific yew that feature a taxadiene core (taxanes).
Binding of paclitaxel to the taxane site induces a conformational change of beta-tubulin that enhances protofilament contacts, leading to microtubule stabilization and suppression of microtubule dynamics.
To quantify the binding site similarity, shared microenvironments between two protein-ligand pockets were used to determine a Pocket Feature Score (PFS), which indicates the likelihood that the ligand from the screened protein pockets will interact with the taxane site.
In silico binding site similarity screen identifies tubulin-ER cross-reactivity.
For example, the two hydroxyl phenyl rings of SERMs and paclitaxel were found in a similar position.
Our initial structural analysis suggested that these functional groups may contribute to similar intermolecular interactions and cause cross-reactivity between the two targets, unexpected from previous work (Fig. To further determine if estrogen modulators in general exhibit potential cross-activity to the beta-tubulin, we evaluated the binding site similarity between the taxane site and 144 ERs, co-crystallized with diverse ER ligands, identified from PDB (Supplementary Data 3).
Although paclitaxel and the second-generation docetaxel (Taxotere, Aventis, Bridgewater, NJ) are two of the most successful chemotherapies for the treatment of breast, ovarian, lung carcinomas, and other malignancies, their clinical use is hampered by drug resistance, hypersensitivity reaction to the drug vehicle, dose-limiting toxicity associated with neurotoxicity, myelosuppression, and other severe side effects.
Furthermore, most taxane drugs, both semisynthetic analogues of paclitaxel and natural products, have higher molecular weight than paclitaxel, are impractical for oral administration, and offer no improvement in clinical performance over the original compounds.
In this study, a computational binding site similarity screen of 14,000 drug-like pockets from PDB reveal an unexpected similarity between the estrogen receptor (ER) and the beta-tubulin taxane binding pocket.
Evaluation of nine selective estrogen receptor modulators (SERMs) via in vivo and in vitro assays confirmed taxane site interaction, microtubule stabilization, and cell proliferation inhibition.