A5078864876- Computational Drug Discovery Methods
- HIV/AIDS drug development and treatment
- Chemical Synthesis and Analysis
- HIV Research and Treatment
- Machine Learning in Materials Science
- Biochemical and Molecular Research
- DNA and Nucleic Acid Chemistry
- Analytical Chemistry and Chromatography
- Click Chemistry and Applications
- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Protein Kinase Regulation and GTPase Signaling
- Pharmacogenetics and Drug Metabolism
- History and advancements in chemistry
- Metabolomics and Mass Spectrometry Studies
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- X-ray Diffraction in Crystallography
- Microbial Natural Products and Biosynthesis
- Advanced Chemical Physics Studies
- Chemical Reaction Mechanisms
- RNA and protein synthesis mechanisms
- Crystallization and Solubility Studies
- Cancer therapeutics and mechanisms
- Fullerene Chemistry and Applications
National Cancer Institute
2015-2024
Center for Cancer Research
2015-2024
Frederick National Laboratory for Cancer Research
2012-2024
National Institutes of Health
2009-2021
National Cancer Institute
2019-2020
Frederick Community College
2018
United States Department of Health and Human Services
2004-2015
Guangzhou Institutes of Biomedicine and Health
2010
Institute of Zoology
2010
South China University of Technology
2010
Background:Humans are exposed to thousands of man-made chemicals in the environment. Some mimic natural endocrine hormones and, thus, have potential be disruptors. Most these never been tested for their ability interact with estrogen receptor (ER). Risk assessors need tools prioritize evaluation costly vivo tests, instance, within U.S. EPA Endocrine Disruptor Screening Program.Objectives:We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity...
The application of the program PASS (Prediction Activity Spectra for Substances) to about 250 000 compounds NCI Open Database and incorporation over 64 million predictions in Enhanced Browser are described. A total 565 different types activity included, encompassing general pharmacological effects, specific mechanisms action, known toxicities, others. Application this Web-based service prediction activities kinds "Angiogenesis inhibitor," "Antiviral (HIV)", a set that can be associated with...
Eight large chemical databases have been analyzed and compared to each other. Central this comparison is the open National Cancer Institute (NCI) database, consisting of approximately 250 000 structures. The other are Available Chemicals Directory ("ACD," from MDL, release 1.99, 3D-version); ChemACX ("ACX," CamSoft, Version 4.5); Maybridge Catalog Asinex database (both as distributed by CamSoft part ChemInfo Sigma-Aldrich (CD-ROM, 1999 Version); World Drug Index ("WDI," Derwent, version...
Seventeen lichen acids comprising despides, depsidones, and their synthetic derivatives have been examined for inhibitory activity against HIV-1 integrase, two pharmacophores associated with inhibition of this enzyme identified. A search the NCI 3D database approximately 200,000 structures yielded some 800 compounds which contain one or other pharmacophore. Forty-two these were assayed integrase inhibition, these, 27 had IC50 values less than 100 microM; 15 below 50 microM. Several also...
Until recently most scientific and patent documents dealing with chemistry have described molecular structures either systematic names or graphical images of Kekulé structures. The latter method poses inherent problems in the automated processing that is needed when number ranges hundreds thousands even millions since representations cannot be directly interpreted by a computer. To recover this structural information, which otherwise all but lost, we built an optical structure recognition...
Knowledge of the possible ionization states a pharmaceutical substance, embodied in pKa values (logarithm acid dissociation constant), is vital for understanding many properties essential to drug development. We compare nine commercially available or free programs predicting constants. Eight these are based on empirical methods: ACD/pKa DB 12.0, ADME Boxes 4.9, ADMET Predictor 3.0, Epik 1.6, Marvin 5.1.4, Pallas pKalc Net 2.0, Pipeline Pilot 5.0, and SPARC 4.2; one program quantum chemical...
Many of the structures in PubChem are annotated with activities determined high-throughput screening (HTS) assays. Because nature these assays, activity data typically strongly imbalanced, a small number active compounds contrasting very large inactive compounds. We have used several such imbalanced HTS assays to test and develop strategies efficiently build robust QSAR models from sets. Different descriptor types [Quantitative Neighborhoods Atoms (QNA) "biological" descriptors] were...
Computational methods to predict molecular properties regarding safety and toxicology represent alternative approaches expedite drug development, screen environmental chemicals, thus significantly reduce associated time costs. There is a strong need interest in the development of computational that yield reliable predictions toxicity, many approaches, including recently introduced deep neural networks, have been leveraged towards this goal. Herein, we report on collection, curation,...
The 4-aryl-2-hydroxy-4-oxo-2-butenoic acids and their isosteric tetrazoles are among an emerging class of aryl beta-diketo (ADK)-based agents which exhibit potent inhibition HIV-1 integrase (IN)-catalyzed strand transfer (ST) processes, while having much reduced potencies against 3'-processing (3'-P) reactions. In the current study, L-708,906 (10e) 5CITEP (13b), two examples ADK inhibitors that have been reported by Merck Shionogi pharmaceutical companies, served as model leads. Structural...
Starting from a known inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN); caffeic acid phenethyl ester (CAPE), putative three-point pharmacophore for binding inhibitors to IN was derived. This used search the National Cancer Institute three-dimensional (3D) structural database. Out open, nonproprietary part this database, comprising approximately 200000 compounds, 267 structures were found match in at least one conformation, and 60 those tested an vitro assay against...
The human immunodeficiency virus type one integrase (HIV-1 integrase) is required for integration of a double-stranded DNA copy the viral RNA genome into host chromosome and HIV replication. We have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE), tyrphostins, curcumin confer inhibitory activity against HIV-1 integrase. investigated actions several recently described protease inhibitors, possessing novel structural features, on...
A Sagnac experiment with electron waves in vacuum is reported. The phase shift caused by rotation of an biprism interferometer placed on a turntable has been measured. It was found to agree prediction within error margins about 30%. compact ruggedized used. based high-precision optical bench 36-cm length. This less sensitive orders magnitude mechanical vibrations and electromagnetic stray fields than conventional interferometers. beam low-energy electrons (150--3000 eV) emitted...
The β-diketo acids (DKAs) represent a major advance for anti–HIV-1 integrase drug development. We compared the inhibition of HIV-1 by six DKA derivatives using wild-type enzyme or double-mutant F185K/C280S, which has been previously used crystal structure determinations. With enzyme, we found that DKAs could be classified into two groups: those similarly potent in presence magnesium and manganese relatively ineffective magnesium. Both aromatic carboxylic tetrazole functions determined their...
A searcheable database of three-dimensional structures has been developed from the chemistry NCI Drug Information System (DIS), a file about 450,000 primarily organic compounds which have tested by for anticancer activity. The DIS is very similar in size and content to proprietary databases used pharmaceutical industry; its development began 1950s; this history led number problems generation 3D structures.
Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in U.S. with more than 100 000 deaths per year. As up to 30% all ADRs believed be caused by drug–drug interactions (DDIs), typically mediated cytochrome P450s, possibilities predict DDIs from existing knowledge important. We collected data public sources on 1485, 2628, 4371, and 27 966 possible four P450 isoforms 1A2, 2C9, 2D6, 3A4 for 55, 73, 94, 237 drugs, respectively. For each these sets, we developed validated...
C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP represents most potent selective small molecule KAT inhibitor identified to date. To gain insights into cellular activity of this epigenetic probe, we applied chemoproteomics identify covalent targets chemotype. Modeling synthetic derivatization was used develop a clickable analogue (C646-yne) that similarly parent compound enables enrichment bound proteins. LC–MS/MS major C646-yne as highly abundant cysteine-containing...
Abstract We have made available a database of over 1 billion compounds predicted to be easily synthesizable, called Synthetically Accessible Virtual Inventory (SAVI). They been created by set transforms based on an adaptation and extension the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from LHASA project. The chemoinformatics toolkit CACTVS was used apply total 53 about 150,000 readily building blocks (enamine.net). Only...
Fifteen novel non-peptide HIV-1 protease inhibitors were identified by flexible 3D database pharmacophore searching of the NCI DIS database. The query used in search was derived directly from X-ray determined structures protease/inhibitor complexes. These 15 inhibitors, belonging to nine different chemical classes, are promising leads for further development. two best found, NSC 32180, a "dimer" 4-hydroxycoumarin, and 117027, "tetramer" 2-hydroxy quinone, had ID50 values 0.32 0.75 microM...
A Web-based, graphical user interface has been developed to conduct rapid searches by numerous criteria in the more than 250,000 structures of Open NCI Database. It is based on chemistry information toolkit CACTVS. Nearly all and anticancer anti-HIV screening data provided NCI's Developmental Therapeutics Program have included. This set augmented a large amount additional, mostly computed, data, such as calculated log P values, predicted biological activities, systematically determined...