The Chemical Space of Flavours

The flavour of foods is determined by the interaction of taste molecules with receptors in the mouth, and fragrances or aroma with receptors in the upper part of the nose. Here, we discuss the properties of taste and fragrance molecules, from the public databases Superscent, Flavornet, SuperSweet and BitterDB, taken collectively as flavours, in the perspective of the chemical space. We survey simple descriptor profiles in comparison with the public collections ChEMBL (bioactive small molecules), ZINC (commercial drug-like molecules) and GDB-13 (all possible organic molecules up to 13 atoms of C, N, O, S, Cl). A global analysis of the chemical space of flavours is also presented based on molecular quantum numbers (MQN) and SMILES fingerprints (SMIfp). While taste molecules span a very broad property range, fragrances occupy a narrow area of the chemical space consisting of generally very small and relatively nonpolar molecules distinct of standard drug molecules. Proximity searching in the chemical space is exemplified as a simple method to facilitate the search for new fragrances

Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

Drug, molecules consist of a few tens of atoms connected by covalent bonds. Haw many such molecules are possible in total and what is their structure? This question is of pressing interest in: medicinal. chemistry to help solve the problems of drug potency, selectivity, and toxicity and reduce attrition rates by pointing to new molecular series. To better define the unknown chemical space, we have enumerated 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens forming the Chemical-universe. database GDB-17, covering a size range containing many drugs and typical for lead compounds. GDB-17 contains Millions of isomers of known drugs,. including analogs: with high, shape : similarity to the parent drug. Compared to known molecules in PubChem, GDB-17 molecules are much richer in nonaromatic hetero- cycles, quaternary centers, and stereoisomers, densely populate the third dimension in shape space and represent many more scaffold types

Visualization and Virtual Screening of the Chemical Universe Database GDB-17

The chemical universe database GDB-17 contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens obeying rules for chemical stability, synthetic feasibility, and medicinal chemistry. GDB-17 was analyzed using 42 integer value descriptors of molecular structure which we term “Molecular Quantum Numbers” (MQN). Principal component analysis and representation of the (PC1, PC2)-plane provided a graphical overview of the GDB-17 chemical space. Rapid ligand-based virtual screening (LBVS) of GDB-17 using the city-block distance CBD_MQN as a similarity search measure was enabled by a hashed MQN-fingerprint. LBVS of the entire GDB-17 and of selected subsets identified shape similar, scaffold hopping analogs (ROCS > 1.6 and <i>T</i>_SF < 0.5) of 15 drugs. Over 97% of these analogs occurred within CBD_MQN ≤ 12 from each drug, a constraint which might help focus advanced virtual screening. An MQN-searchable 50 million subset of GDB-17 is publicly available at www.gdb.unibe.ch

Biochanin A and prunetin improve epithelial barrier function in intestinal CaCo-2 cells via downregulation of ERK, NF-κB, and tyrosine phosphorylation

The single-layered gut epithelium represents the primary line of defense against environmental stressors; thereby monolayer integrity and tightness are essentially required to maintain gut health and function. To date only a few plant-derived phytochemicals have been described as affecting intestinal barrier function. We investigated the impact of 28 secondary plant compounds on the barrier function of intestinal epithelial CaCo-2/TC-7 cells via transepithelial electrical resistance (TEER) measurements. Apart from genistein, the compounds that had the biggest effect in the TEER measurements were biochanin A and prunetin. These isoflavones improved barrier tightness by 36 and 60%, respectively, compared to the untreated control. Furthermore, both isoflavones significantly attenuated TNFα-dependent barrier disruption, thereby maintaining a high barrier resistance comparable to nonstressed cells. In docking analyses exploring the putative interaction with the tyrosine kinase EGFR, these novel modulators of barrier tightness showed very similar values compared to the known tyrosine kinase inhibitor genistein. Both biochanin A and prunetin were also identified as potent reducers of NF-κB and ERK activation, zonula occludens 1 tyrosine phosphorylation, and metalloproteinase-mediated shedding activity, which may account for the barrier-improving ability of these isoflavones