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The interactions of epothilone analogs with the paclitaxel binding site of microtubules were studied. The influence of chemical modifications in the C15 side chain and in C12 on binding affinity and microtubule elongation was characterized. Modifications favorable for binding affinity are (1). a thiomethyl group at C21 of the thiazole side chain, (2). a methyl group at C12 in S configuration, (3). a pyridine side chain with C15 in S configuration, and (4). a cyclopropyl moiety between C12 and C13. The same modification in different ligands has similar effect on affinity, allowing good structure-affinity characterization. The correlation between binding, microtubule stabilization, and cytotoxicity of the compounds has been determined, showing differential effects of the modifications. The binding constants correlate well with IC(50) values, demonstrating that affinity measurements are a useful tool for drug design.
Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.
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