Biomedical subjects

Yaxiong Sun

Publications and source records attributed to Yaxiong Sun.

5 recordsLinked to original sources

PubMed2006

ADAAPT: Amgen's data access, analysis, and prediction tools.

The Amgen's Data Access Analysis Prediction Tools (ADAAPT) system is a desktop decision support tool developed to provide flexible access and analysis of chemical and biological data. The system is platform independent, adaptable, easily deployed, and scalable. It consists of four main modules: access, analysis, prediction, and tools. The access module contains numerous user interfaces designed to retrieve data easily. The analysis module provides standard computational tools to perform property calculation, QSAR/QSPR, and statistical analyses. The prediction module contains in-house models to calculate a drug-likeness score and absorption index. Finally, the tools module provides a wide array of features that are of general interest to our scientists.

Computer Systems↗

PubMed2004

Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion.

Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a "trimer-of-hairpins" structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.

Amino Acid Sequence↗

PubMed2003

One-pot microwave assisted preparation of pyrazoloquinazolinone libraries.

The novel solution-phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven one pot procedure is revelaed. Transformations are carried out in good to excellent yield by condensation of alpha-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic and enabling complexity generating chemistries in the lead discovery arena.

Chemistry, Organic↗

PubMed2002

Knowledge-based approaches in the design and selection of compound libraries for drug discovery.

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.

Animals↗

PubMedDate not supplied

FLAME: a program to flexibly align molecules.

Herein, we describe a method to flexibly align molecules (FLAME = FLexibly Align MolEcules). FLAME aligns two molecules by first finding maximum common pharmacophores between them using a genetic algorithm. The resulting alignments are then subjected to simultaneous optimizations of their internal energies and an alignment score. The utility of the method in pairwise alignment, multiple molecule flexible alignment, and database searching was examined. For pairwise alignment, two carboxypeptidase ligands (Protein Data Bank codes and ), two estrogen receptor ligands ( and ), and two thrombin ligands ( and ) were used as test sets. Alignments generated by FLAME starting from CONCORD structures compared very well to the X-ray structures (average root-mean-square deviation = 0.36 A) even without further minimization in the presence of the protein. For multiple flexible alignments, five structurally diverse D3 receptor ligands were used as a test set. The FLAME alignment automatically identified three common pharmacophores: a base, a hydrogen-bond acceptor, and a hydrophobe/aromatic ring. The best alignment was then used to search the MDDR database. The search results were compared to the results using atom pair and Daylight fingerprint similarity. A similar database search comparison was also performed using estrogen receptor modulators. In both cases, hits identified by FLAME were structurally more diverse compared to those from the atom pair and Daylight fingerprint methods.

Journal Article↗