An Extensive and Diverse Set of Molecular Overlays for the Validation of Pharmacophore Programs

The pharmacophore hypothesis plays a central role in both the design and optimization of drug-like ligands. Pharmacophore patterns are invoked to explain the binding affinity of ligands and to enable the design of chemically distinct scaffolds that show affinity for a protein target of interest. The importance of pharmacophores in rationalizing ligand affinity has led to numerous algorithms that seek to overlay ligands based on their pharmacophoric features. All such algorithms must be validated with respect to known ligand overlays, usually by extracting ligand overlay sets from the Protein Data Bank (PDB). This validation step creates the problem of which of the known overlays to select and from which proteins. The large number of structures and protein families in the PDB makes it difficult to establish a definitive overlay set; as a result, validation studies have rarely employed the same data sets. We have therefore undertaken an exhaustive analysis of the RCSB PDB to identify 121 distinct ligand overlay sets. We have defined a robust protein overlay protocol, which is free from subjective interpretation over which residues to include, and we have analyzed each overlay set on the basis of whether they provide evidence for the pharmacophore hypothesis. Our final data set spans a broad range of structural types and degrees of difficulty and includes overlays that any algorithm should be able to reproduce, as well as some for which there is very weak evidence for a conserved pharmacophore at all. We provide this set in the hope that it will prove definitive, at least until the PDB is greatly enriched with further structures or with radically different protein folds and families. Upon publication, the data set will be available for free download from the Web site of the Cambridge Crystallographic Data Centre

Assessment of a Cambridge Structural Database-Driven Overlay Program

We recently published an improved methodology for overlaying multiple flexible ligands and an extensive data set for validating pharmacophore programs. Here, we combine these two developments and present evidence of the effectiveness of the new overlay methodology at predicting correct superimpositions for systems with varying levels of complexity. The overlay program was able to generate correct predictions for 95%, 73%, and 39% of systems classified as easy, moderate, and hard, respectively

Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4‑[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (<b>1</b>) to the development candidate AZD8329 (<b>27</b>). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability

Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)

Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound <b>11i</b> (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4–11 cells with an IC₅₀ of 3 μM after 6 h