Biomedical subjects

Suxin Zheng

Publications and source records attributed to Suxin Zheng.

9 recordsLinked to original sources

PubMed2007

Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.

Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.

Animals↗

PubMed2006

Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B.

Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.

Acetylcholinesterase↗

PubMed2006

Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations.

Some structural insights into the conformations of the isonucleosides containing duplexes have been provided. Unrestrained molecular-dynamics simulations on 18-mer duplexes with isonucleosides incorporated at the 3'-end or in the center of one strand have been carried out with explicit solvent under periodic boundary conditions using the AMBER force field and the particle mesh Ewald method. The Watson-Crick hydrogen-bonding patterns of the duplexes studied remained intact throughout the simulation. For the modified duplexes, the changes observed in the inter-base pair parameters and backbone torsional angles were primarily localized at the isonucleoside-inserted area. All five structures studied remained in the B-form family. The decreased stacking abilities indicated by the large changes in inter-base pair parameters and the large changes in backbones made the modified duplexes show a minor thermal destabilization in comparison with native DNA. The MM_PBSA method for estimating binding free energies on two complementary strands was used. The results showed that the binding free energies of isonucleoside-incorporated DNA duplexes were lower than the native DNA duplex, which is in good agreement with experimental observations.

Computer Simulation↗

PubMed2005

Computational analysis of molecular basis of 1:1 interactions of NRG-1beta wild-type and variants with ErbB3 and ErbB4.

The neuregulin/ErbB system is a growth factor/receptor cascade that has been proven to be essential in the development of the heart and the sympathetic nervous system. However, the basis of the specificity of ligand-receptor recognition remains to be elucidated. In this study, the structures of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes were modeled based on the available structures of the homologous proteins. The binding free energies of NRG-1beta to ErbB3 and ErbB4 were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) computational method. In addition, computational alanine-scanning mutagenesis was performed in the binding site of NRG-1beta and the difference in the binding free energies between NRG-1beta mutants and the receptors was calculated. The results specify the contribution of each residue at the interaction interfaces to the binding affinity of NRG-1beta with ErbB3 and ErbB4, identifying several important interaction residue pairs that are in agreement with previously acquired experimental data. This indicates that the presented structural models of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes are reliable and could be used to guide future studies, such as performing desirable mutations on NRG-1beta to increase the binding affinity and selectivity to the receptor and discovering new therapeutic agents for the treatment of heart failure.

Alanine↗

PubMed2005

Bis-huperzine B: highly potent and selective acetylcholinesterase inhibitors.

By targeting dual active sites of AChE, a series of bis-huperzine B analogues with various lengths of the tether were designed, synthesized, and tested for their inhibition and selectivity. The most potent bis-huperzine B (5g) exhibited 3900-fold increase in AChE inhibition and 930-fold greater in selectivity for AChE vs BuChE than its parent huperzine B.

Acetylcholinesterase↗

PubMed2004

Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for SARS infection. Nucleocapsid protein (NP) of SARS-CoV (SARS_NP) functions in enveloping the entire genomic RNA and interacts with viron structural proteins, thus playing important roles in the process of virus particle assembly and release. Protein-protein interaction analysis using bioinformatics tools indicated that SARS_NP may bind to human cyclophilin A (hCypA), and surface plasmon resonance (SPR) technology revealed this binding with the equilibrium dissociation constant ranging from 6 to 160nM. The probable binding sites of these two proteins were detected by modeling the three-dimensional structure of the SARS_NP-hCypA complex, from which the important interaction residue pairs between the proteins were deduced. Mutagenesis experiments were carried out for validating the binding model, whose correctness was assessed by the observed effects on the binding affinities between the proteins. The reliability of the binding sites derived by the molecular modeling was confirmed by the fact that the computationally predicted values of the relative free energies of the binding for SARS_NP (or hCypA) mutants to the wild-type hCypA (or SARS_NP) are in good agreement with the data determined by SPR. Such presently observed SARS_NP-hCypA interaction model might provide a new hint for facilitating the understanding of another possible SARS-CoV infection pathway against human cell.

Amino Acid Sequence↗

PubMed2003

Structure-based discovery of potassium channel blockers from natural products: virtual screening and electrophysiological assay testing.

Potassium ion (K(+)) channels are attractive targets for rational drug design. Based upon a three-dimensional model of the eukaryotic K(+) channels, the docking virtual screening approach was employed to search the China Natural Products Database. Compounds were ranked according to the relative binding energy, favorable shape complementarity, and potential of forming hydrogen bonds with the K(+) channel. Four candidate compounds found by virtual screening were investigated by using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. When applied extracellularly, compound 1 markedly depressed the delayed rectifier K(+) current (I(K)) and fast transient K(+) current (I(A)), whereas compounds 2, 3, and 4 exerted a more potent and selective inhibitory effect on I(K). Intracellular application of the four compounds had no effect on both the K(+) currents.

Animals↗

PubMedDate not supplied

Focused combinatorial library design based on structural diversity, druglikeness and binding affinity score.

The advent of focused library and virtual screening has reduced the disadvantage of combinatorial chemistry and changed it to a realizable and cost-effective tool in drug discovery. Usually, genetic algorithms (GAs) are used to quickly finding high-scoring molecules by sampling a small subset of the total combinatorial space. Therefore, scoring functions play essential roles in focused library design. Reported here is our initial attempt to establish a new approach for generating a target-focused library using the combination of the scores of structural diversity and binding affinity with our newly improved drug-likeness scoring functions. Meanwhile, a software package, named LD1.0, was developed on the basis of the new approach. One test on a cyclooxygenase (COX)2-focused library successfully reproduced the structures that have been experimentally studied as COX2-selective inhibitors. Another test is on a peroxisome proliferator-activated receptors gamma-focused library design, which not only reproduces the key fragments in the approved (thiazolidinedione) TZD drugs, but also generates some new structures that are more active than the approved drugs or published ligands. Both of the two tests took approximately 15% of the running time of the ordinary molecular docking method. Thus, our new approach is an effective, reliable, and practical way for building up a properly sized focused library with a high hit rate, novel structure, and good ADME/T profile.

Algorithms↗

PubMedDate not supplied

A new rapid and effective chemistry space filter in recognizing a druglike database.

To develop a new chemistry space filter with high efficiency and accuracy, an analysis on distributions of as many as 50 structural and physicochemical properties was carried out on both druglike and nondruglike databases, viz. MACCS-II Drug Data Report (MDDR), Comprehensive Medicinal Chemistry (CMC), and Available Chemicals Directory (ACD). Based on the analysis results, a chemistry space filter was developed that can effectively discriminate a druglike database from a nondruglike database. The filter is composed of two descriptors: one is a molecular saturation related descriptor, and the other is associated with the proportion of heteroatoms in a molecule. Both are molecular size independent. Therefore, the profiles of a druglike database could be characterized as proper molecular saturation and proper percentage of heteroatoms, revealing direct indices for designing and optimizing combinatorial libraries. The application of the new filter on the Chinese Natural Product Database (CNPD) suggested that CNPD is, as expected, a potential druglike database, testifying that the new filter is reliable. Therefore, this newly developed chemistry space filter should be a potent tool for identifying druglike molecules, thus, it would have potential applications in the research of combinatorial library design and virtual high throughput screening using computational approaches for drug discovery.

Combinatorial Chemistry Techniques↗