Abstract:
:Advances in the development of high-throughput screening and automated chemistry have rapidly accelerated the production of chemical and biological data, much of them freely accessible through literature aggregator services such as ChEMBL and PubChem. Here, we explore how to use this comprehensive mapping of chemical biology space to support the development of large-scale quantitative structure-activity relationship (QSAR) models. We propose a new deep learning consensus architecture (DLCA) that combines consensus and multitask deep learning approaches together to generate large-scale QSAR models. This method improves knowledge transfer across different target/assays while also integrating contributions from models based on different descriptors. The proposed approach was validated and compared with proteochemometrics, multitask deep learning, and Random Forest methods paired with various descriptors types. DLCA models demonstrated improved prediction accuracy for both regression and classification tasks. The best models together with their modeling sets are provided through publicly available web services at https://predictor.ncats.io .
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Zakharov AV,Zhao T,Nguyen DT,Peryea T,Sheils T,Yasgar A,Huang R,Southall N,Simeonov Adoi
10.1021/acs.jcim.9b00526subject
Has Abstractpub_date
2019-11-25 00:00:00pages
4613-4624issue
11eissn
1549-9596issn
1549-960Xjournal_volume
59pub_type
杂志文章abstract::DNA damage alters genetic information and adversely affects gene expression pathways leading to various complex genetic disorders and cancers. DNA repair proteins recognize and rectify DNA damage and mismatches with high fidelity. A critical molecular event that occurs during most protein-mediated DNA repair processes...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00636
更新日期:2018-03-26 00:00:00
abstract::We examine the sensitivity of folding molecular dynamics simulations on the choice between three variants of the same force field (the AMBER99SB force field and its ILDN, NMR-ILDN, and STAR-ILDN variants). Using two different peptide systems (a marginally stable helical peptide and a β-hairpin) and a grand total of mo...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00493
更新日期:2016-10-24 00:00:00
abstract::Reversible and irreversible covalent ligands are advanced cysteine protease inhibitors in the drug development pipeline. K777 is an irreversible inhibitor of cruzain, a necessary enzyme for the survival of the Trypanosoma cruzi (T. cruzi) parasite, the causative agent of Chagas disease. Despite their importance, irrev...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b01138
更新日期:2020-03-23 00:00:00
abstract::The Torsion Library contains hundreds of rules for small molecule conformations which have been derived from the Cambridge Structural Database (CSD) and are curated by molecular design experts. The torsion rules are encoded as SMARTS patterns and categorize rotatable bonds via a traffic light coloring scheme. We have ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00522
更新日期:2016-01-25 00:00:00
abstract::Classical nonpolarizable models, normally based on a combination of Lennard-Jones sites and point charges, are extensively used to model thermodynamic properties of fluids, including solvation. An important shortcoming of these models is that they do not explicitly account for polarization effects, i.e., a description...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b01005
更新日期:2020-03-23 00:00:00
abstract::The viral NS5B RNA-dependent RNA-polymerase (RdRp) is one of the best-studied and promising targets for the development of novel therapeutics against hepatitis C virus (HCV). Allosteric inhibition of this enzyme has emerged as a viable strategy toward blocking replication of viral RNA in cell based systems. Herein, we...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci9004749
更新日期:2010-04-26 00:00:00
abstract::Spin diffusion is a formidable problem when interpreting NMR data of chemical compounds. We developed a method to reconstruct the conformational ensemble of flexible molecules displaying spin diffusion, which minimizes the subjective bias in the interpretation of experimental data and which can be used routinely to ob...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00259
更新日期:2019-06-24 00:00:00
abstract::The interaction between small molecules and proteins is one of the major concerns for structure-based drug design because the principles of protein-ligand interactions and molecular recognition are not thoroughly understood. Fortunately, the analysis of protein-ligand complexes in the Protein Data Bank (PDB) enables u...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100386y
更新日期:2011-04-25 00:00:00
abstract::The second extracellular loops (ECL2s) of G-protein-coupled receptors (GPCRs) are often involved in GPCR functions, and their structures have important implications in drug discovery. However, structure prediction of ECL2 is difficult because of its long length and the structural diversity among different GPCRs. In th...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00148
更新日期:2018-06-25 00:00:00
abstract::The human androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of prostate cancer (PCa). Many forms of castration-resistant prostate cancer (CRPC) still rely on the AR for survival. Currently used antiandrogens face clinical limitations as drug ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00400
更新日期:2016-12-27 00:00:00
abstract::3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is a primary target in the current clinical treatment of hypercholesterolemia with specific inhibitors of "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzyme, which are well-known as...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300163v
更新日期:2012-07-23 00:00:00
abstract::The early stages of drug discovery rely on hit-to-lead programs, where initial hits undergo partial optimization to improve binding affinities for their biological target. This is an expensive and time-consuming process, requiring multiple iterations of trial and error designs, an ideal scenario for applying computer ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00938
更新日期:2020-03-23 00:00:00
abstract::DiSCuS, a "Database System for Compound Selection", has been developed. The primary goal of DiSCuS is to aid researchers in the steps subsequent to generating high-throughput virtual screening (HTVS) results, such as selection of compounds for further study, purchase, or synthesis. To do so, DiSCuS provides (1) a stor...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400587f
更新日期:2014-01-27 00:00:00
abstract::Inhibitors of histone deacetylases (HDACIs) have emerged as a new class of drugs for the treatment of human cancers and other diseases because of their effects on cell growth, differentiation, and apoptosis. In this study we have developed several quantitative structure-activity relationship (QSAR) models for 59 chemi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800366f
更新日期:2009-02-01 00:00:00
abstract::Methods that rapidly evaluate molecular complexity and synthetic feasibility are becoming increasingly important for in silico chemistry. We propose a new metric based on relative atomic electronegativities and bond parameters that evaluate both synthetic and molecular complexity (SMCM) starting from chemical structur...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci0501387
更新日期:2005-09-01 00:00:00
abstract::A database of about 700 high-resolution kinase structures was used to test the reliability of 17 docking procedures (using six docking software packages) by means of self- and cross-docking studies. The analysis of about 80 000 docking calculations suggests that the docking of an unknown ligand into a kinase has a pro...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100161z
更新日期:2010-08-23 00:00:00
abstract::This article presents the computation of both inter- and intramolecular hydrogen bond strengths from first-principles. Quantum chemical calculations conducted at the dispersion-corrected density functional theory level including free energy and solvation contributions are conducted for (i) one-to-one hydrogen-bonded c...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00132
更新日期:2019-09-23 00:00:00
abstract::When both the difference between two quantities and their individual values can be measured or computationally predicted, multiple quantities can be determined from the measurements or predictions of select individual quantities and select pairwise differences. These measurements and predictions form a network connect...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00528
更新日期:2019-11-25 00:00:00
abstract::Most drugs exert their effects via multitarget interactions, as hypothesized by polypharmacology. While these multitarget interactions are responsible for the clinical effect profiles of drugs, current methods have failed to uncover the complex relationships between them. Here, we introduce an approach which is able t...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci2002022
更新日期:2012-01-23 00:00:00
abstract::The efficiency of automated compound screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their p...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300382f
更新日期:2013-03-25 00:00:00
abstract::Understanding the relationship between chemical structure and function is a ubiquitous problem within the fields of chemistry and biology. Simulation approaches attack the problem utilizing physics to understand a given process at the particle level. Unfortunately, these approaches are often too expensive for many pro...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci8001233
更新日期:2008-08-01 00:00:00
abstract::A new variable selection wrapper method named the Monte Carlo variable selection (MCVS) method was developed utilizing the framework of the Monte Carlo cross-validation (MCCV) approach. The MCVS method reports the variable selection results in the most conventional and common measure of statistical hypothesis testing,...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700283s
更新日期:2008-02-01 00:00:00
abstract::There are only four derivatives of pseudouridine (Ψ) that are known to occur naturally in RNA as post-transcriptional modifications. We have studied the conformational consequences of pseudouridylation and further modifications using replica exchange molecular dynamics simulations at the nucleoside level, and the simu...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00369
更新日期:2020-10-26 00:00:00
abstract::The number of journal articles in the scientific domain has grown to the point where it has become impossible for researchers to capitalize on all findings in their relevant discipline. Information is stored in these articles in a number of ways, including figures that describe important results. In organic chemistry,...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00042
更新日期:2020-04-27 00:00:00
abstract::We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judg...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00618
更新日期:2018-04-23 00:00:00
abstract::The applicability and scope of 3D QSAR methods (CoMFA, CoMSIA) to screen databases are examined. A protocol requiring minimal user intervention has been established to align training and test set molecules using FlexS. As model system isozymes of human carbonic anhydrase (hCA) are used, all results are exemplified stu...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci7002945
更新日期:2008-02-01 00:00:00
abstract::The primary goal of ligand-based virtual screening is to identify active compounds consisting of a core scaffold that is not found in the current active compound pool. Scaffold hopping is the term used for this purpose. In the present study, topological representations of pharmacophore features on chemical graphs were...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00098
更新日期:2020-04-27 00:00:00
abstract::Dual and triple activity-difference (DAD/TAD) maps are tools for the systematic characterization of structure-activity relationships (SAR) of compound data sets screened against two or three targets. DAD and TAD maps are two- and three- dimensional representations of the pairwise activity differences of compound data ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci200281v
更新日期:2011-09-26 00:00:00
abstract::The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pr...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00254
更新日期:2020-11-23 00:00:00
abstract::Protein-protein interactions (PPIs) play vital roles in regulating biological processes, such as cellular and signaling pathways. Hotspots are certain residues located at protein-protein interfaces that contribute more in protein-protein binding than other residues. Research on the mutational effects of hotspots is im...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00966
更新日期:2021-01-25 00:00:00