Biomedical subjects

I-Jen Chen

Publications and source records attributed to I-Jen Chen.

3 recordsLinked to original sources

PubMed2004

A structure-based strategy to identify new molecular scaffolds targeting the bacterial ribosomal A-site.

The need for novel antibiotics is widely recognized. A well validated target of antibiotics is the bacterial ribosome. Recent X-ray structures of the ribosome bound to antibiotics have shed new light on the binding sites of these antibiotics, providing fresh impetus for structure-based strategies aiming at identifying new ribosomal ligands. In that respect, the ribosomal decoding region of the aminoacyl-tRNA acceptor site (A-site) is of particular interest because oligonucleotide model systems of this site are available for crystallography, NMR and compound binding assays. This work presents how these different resources can be combined in a hierarchical screening strategy which has led to the identification of new A-site ligands. The approach exploits an X-ray structure of the A-site against which large and diverse libraries of compounds were computationally docked. The complementarity of the compounds to the A-site was assessed using a scoring function specifically calibrated for RNA targets. Starting from approximately 1 million compounds, the computational selection of candidate ligands allowed us to focus the experimental work on 129 compounds, 34 of which showed affinity for the A-site in a FRET-based binding assay. NMR experiments confirmed binding to the A-site for some compounds. For the most potent compound in the FRET assay, a tentative binding mode is suggested, which is compatible with the NMR data and the limited SAR in this series. Overall, the results validate the screening strategy.

Anti-Bacterial Agents↗

PubMed2002

Structure-based inhibitor design targeting HIV-1 integrase.

HIV integrase (IN) is a viral-encoded protein that catalyzes the breaking and joining reactions that mediate integration of viral DNA into the host genome. Therefore, IN offers a unique target for the development of novel anti-HIV and anti-AIDS therapeutics. To take advantage of this potential, drug discovery efforts via structure-based design approaches have been undertaken. Presented is a review of computer-aided drug design efforts targeting HIV IN. Included is an overview of the life-cycle of HIV, with emphasis on the mechanism of action of IN, biological assays for measuring IN activity and identifying IN inhibitors, and the appropriate cell-based assays required for determining the antiviral activity of IN inhibitors. This is followed by a review of the available three-dimensional structures of HIV IN. Structure-based drug design efforts are then critiqued, including both ligand-based (e.g. pharmacophore) and target-based (e.g. docking) methods. Results from recent computational chemistry studies of IN are also discussed.

Catalysis↗

PubMedDate not supplied

Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy. Results indicate that the parent pyridine was highly permeable and that chemical substitution was able to reduce pyridine permeability almost 20-fold. The substituent effect on permeability provided the following rank order: 3-COO- < 4-NH2 < 3-CONH2 < 3-Cl < 3-CHO < 3-OH < 3-CH2OH < 3-C6H5 < 3-NH2 < 3-CH2C6H5 < 3-C2H5 < 3-H < 3-CH3 < 3-F < 4-C6H5. This substituent effect was better explained via molecule descriptors from the computational chemistry approach than explained by classic descriptors from Hansch. Computational descriptors indicate that aqueous desolvation, but not membrane partitioning per se, dictated substituent effect on permeability.

Caco-2 Cells↗