Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41.

On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A(1), NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket.

QSPR prediction of GC retention indices for nitrogen-containing polycyclic aromatic compounds from heuristically computed molecular descriptors.

Gas chromatographic retention indices of nitrogen-containing polycyclic aromatic compounds (N-PACs) have been predicted by quantitative structure-property relationship (QSPR) analysis based on heuristic method (HM) implemented in CODESSA. In order to indicate the influence of different molecular descriptors on retention indices and well understand the important structural factors affecting the experimental values, three multivariable linear models derived from three groups of different molecular descriptors were built. Moreover, each molecular descriptor in these models was discussed to well understand the relationship between molecular structures and their retention indices.

Cellular interaction through LewisX cluster: theoretical studies.

It is well known that cell surface carbohydrates play a role in cell-cell adhesion and communication. LewisX glycosphingolipids form microdomains on cell surfaces. Homotypic and calcium-mediated LewisX-LewisX (LeX-LeX) interactions were proposed to be responsible for the initial steps of cell adhesion, and to mediate embryogenesis and metastasis.

Molecular modeling studies of N-substituted pyrrole derivatives--potential HIV-1 gp41 inhibitors.

2D-, 3D-QSAR and docking studies were carried out on 23 pyrrole derivatives, to model their HIV-1 gp41 inhibitory activities. The 2D, 3D-QSAR studies were performed using CODESSA software package and comparative molecular field analysis (CoMFA) technique, respectively. The CODESSA five-descriptor model has a correlation coefficient R(2)=0.

Flexible computational docking studies of new aminoglycosides targeting RNA 16S bacterial ribosome site.

Ribonucleic acids (RNAs) have only recently been viewed as a target for small-molecules drug discovery. Aminoglycoside compounds are antibiotics which bind the ribosomal A site (16S fragment) and cause misreading of the bacterial genetic code and inhibit translocation. In this work, a complete molecular modeling study is done for 16 newly derived aminoglycoside compounds where diverse nucleoside fragments are linked.

MolDiA: a novel molecular diversity analysis tool. 1. Principles and architecture.

We introduce the principles and the architecture of a user-friendly software named MOLDIA (Molecular Diversity Analysis) which aims to the comparison of diverse molecular data sets through an XML structured database of predefined fragments. The MOLDIA descriptors are composed of complex fingerprint-like structures, which enclose not only structural information but also physicochemical property data. The system architecture includes the use of customizable weights on molecular descriptors and different choices of similarity/diversity measures to analyze the given data sets.

Cytotoxicity of cantharidin analogues targeting protein phosphatase 2A.

Cantharidin is a natural toxin that possesses potent anti-tumor properties. Its clinical application, however, is limited due to severe side-effects. Its cytotoxicity is believed to be mediated by the inhibition of serine/threonine protein phosphatase 2A.

QSAR study of 1,4-dihydropyridine calcium channel antagonists based on gene expression programming.

The gene expression programming, a novel machine learning algorithm, is used to develop quantitative model as a potential screening mechanism for a series of 1,4-dihydropyridine calcium channel antagonists for the first time. The heuristic method was used to search the descriptor space and select the descriptors responsible for activity. A nonlinear, six-descriptor model based on gene expression programming with mean-square errors 0.

Molecular similarity and diversity in chemoinformatics: from theory to applications.

This review is dedicated to a survey on molecular similarity and diversity. Key findings reported in recent investigations are selectively highlighted and summarized. Even if this overview is mainly centered in chemoinformatics, applications in other areas (pharmaceutical and medical chemistry, combinatorial chemistry, chemical databases management, etc.

[Studies on quantitative structure-retention relationships for sulfides on stationary phases of different polarities].

Multiple linear regression (MLR) based on forward stepwise multiple regression techniques was used for predicting gas chromatographic retention index of sulfides after calculating their quantum-chemical parameters. The correlative quantitative model between the retention index (IR) of sulfides on four stationary phases of different polarities and their quantum chemical parameters was built. The results proved the strong predictive power of the models.

Design, synthesis, and SAR analysis of cytotoxic sinapyl alcohol derivatives.

Five series totalling 51 of sinapyl alcohol derivatives were designed and synthesized. Their cytotoxicity analyses were performed on six human tumor cell lines such as PC-3, CNE, KB, A549, BEL-7404, and HeLa. Certain sinapyl alcohol derivatives showed significant cytotoxic activities.

Computational studies and drug design for HIV-1 reverse transcriptase inhibitors of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs.

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT.

Activity and QSAR study of baogongteng A and its derivatives as muscarinic agonists.

Baogongteng A (BGT-A), a naturally occurring tropane muscarinic agonist isolated from Chinese medicinal plant, exhibits a bioactive effect different from those of many tropane alkaloids that are muscarinic antagonists. A series of racemic derivatives of BGT-A was synthesized to study the structure-activity relationships (SAR). To explore further the SAR in this series and to ultimately design muscarinic agonists for drug development, a Comparative Molecular Field Analysis (CoMFA) was performed.

Molecular modeling, design, synthesis, and biological evaluation of novel 3',4'-dicamphanoyl-(+)-cis-khellactone (DCK) analogs as potent anti-HIV agents.

Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r(2) values of 0.995 and 0.

"In vitro" protection of DNA from Fenton reaction by plant polyphenol verbascoside.

The protection effect of verbascoside (Ver) against Fenton reaction on plasmid pBR322 DNA was studied using agarose gel electrophoresis and UV-visible spectroscopy. The pBR322 plasmid DNA is damaged by hydroxyl radical (OH*) generated from the Fenton reaction with H2O2 and Fe(II) or Fe(III). This DNA damage is characterized by the diminution of supercoiled DNA forms or by the increase of relaxed or linear DNA forms after oxidative attack.

Discovery of anti-SARS coronavirus drug based on molecular docking and database screening.

The active site of 3CL proteinase (3CL) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CL of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking.

CoMFA/CoMSIA/HQSAR and Docking Study of the Binding Mode of Selective Cyclooxygenase (COX-2) Inhibitors.

The intermolecular interaction between four types of anti-inflammatory inhibitors (oxazoles, pyrazoles, pyrroles and imidazoles) and COX-2 receptor was studied. The results of docking suggest that they have similar interaction mechanism. The most active compounds of these four types of inhibitors could both form several hydrogen bonds with residues His90, Arg513, Leu352 and Arg120, and develop hydrophobic interaction with residues Phe518, Leu352 and Leu359.

Spectral code index (SPECOIND): a general infrared spectral database search method.

A new spectral code that can be used by Relational Database Management Systems (RDBMS) as an index for infrared (IR) spectra searches in Relational Database (RDB) is presented and its suitability is evaluated. Spectral codes are constructed for all spectra in the database as the spectral indexes and three query strings are created with the same theory used for the creation of the index code for the query spectrum. Some effects of parameters used to create index strings and query strings are discussed.

MASSIS: a mass spectrum simulation system. 2: Procedures and performance.

The use of the mass spectral simulation system, MASSIS, is reported and its performance has been evaluated. The search for substructures matching with fragments stored in four pivot databases was realised using the Ullmann algorithm. Special cleavage rules, such as the McLafferty rearrangement, the retro-Diels-Alder reaction, elimination of a neutral small molecule and oxygen migration, are processed through shortest path and depth-first search algorithms.

MASSIS: a mass spectrum simulation system 1. Principle and method.

A mass spectrum simulation system was developed. The simulated spectrum for a given target structure is computed based on the cleavage knowledge and statistical rules established and stocked in pivot databases: cleavage rule knowledge, function groups, small fragments and fragment-intensity relationships. These databases were constructed from correlation charts and statistical analysis of large population of organic mass spectra using data mining techniques.