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Torsten Herbertz

Publications and source records attributed to Torsten Herbertz.

5 recordsLinked to original sources
PubMed2006

Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.

Animals↗
PubMed2006

Knowledge-based chemoinformatic approaches to drug discovery.

The modern drug discovery process is steadily becoming more information driven. Structural, physicochemical and ADME-Tox property profiles of reference (successful) ligands, along with structural information of their target proteins, have been extremely useful for early-stage drug discovery. Recently, databases of known biologically active ligands (knowledge bases) have become more focused toward different protein-target classes. The number of new chemoinformatics tools used to analyze structures and properties of successful molecules has also increased enormously. Scientists in this area are exploring new physicochemical properties and appropriate drug sets to understand druglike properties. In this review, the various uses of the ligand knowledge bases in the drug discovery process have been critically reviewed.

Drug Design↗
PubMed2004

VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds.

Rhinoviruses are the most common infectious agents of humans. They are the principal etiologic agents of afebrile viral upper-respiratory-tract infections (the common cold). Human rhinoviruses (HRVs) comprise a genus within the family Picornaviridae. There are >100 serotypically distinct members of this genus. In order to better understand their phylogenetic relationship, the nucleotide sequence for the major surface protein of the virus capsid, VP1, was determined for all known HRV serotypes and one untyped isolate (HRV-Hanks). Phylogenetic analysis of deduced amino acid sequence data support previous studies subdividing the genus into two species containing all but one HRV serotype (HRV-87). Seventy-five HRV serotypes and HRV-Hanks belong to species HRV-A, and twenty-five HRV serotypes belong to species HRV-B. Located within VP1 is a hydrophobic pocket into which small-molecule antiviral compounds such as pleconaril bind and inhibit functions associated with the virus capsid. Analyses of the amino acids that constitute this pocket indicate that the sequence correlates strongly with virus susceptibility to pleconaril inhibition. Further, amino acid changes observed in reduced susceptibility variant viruses recovered from patients enrolled in clinical trials with pleconaril were distinct from those that confer natural phenotypic resistance to the drug. These observations suggest that it is possible to differentiate rhinoviruses naturally resistant to capsid function inhibitors from those that emerge from susceptible virus populations as a result of antiviral drug selection pressure based on sequence analysis of the drug-binding pocket.

Amino Acid Sequence↗
PubMed1999

Electron Transfer Photochemistry of Homochrysanthemol: Intramolecular Nucleophilic Attack on the Cyclopropane Ring.

The electron-transfer photochemistry of homochrysanthemol, 1, resulted exclusively in intramolecular "substitution" at the quaternary cyclopropane carbon, generating the five-membered cyclic ethers, 2 and 4. The alternative "addition" to the terminal carbon of the double bond, which would result in seven-membered cyclic ethers, 3 and 5, was not observed. Apparently, the five-membered transition state leading to 2 and 4 is significantly favored over the seven-membered one required for formation of 3 and 5. These results stand in interesting contrast to the previously established reaction pattern of chrysanthemol, 8, which is captured exclusively at the terminal vinyl carbon. The divergent regiochemistry of 1(*)(+) and 8(*)(+) (even though the tethers between vinylcyclopropane and alcohol functions differ only by a single CH(2) group) elucidates the principles governing the course of nucleophilic capture in radical cations.

Journal Article↗