Abstract：
:Targeted covalent inhibitors (TCIs) have been successfully developed as high-affinity and selective inhibitors of enzymes of the protein kinase family. These drugs typically act by undergoing an electrophilic addition with an active-site cysteine residue, so design of a TCI begins with the identification of a "druggable" cysteine. These electrophilic additions generally require deprotonation of the thiol to form a reactive anionic thiolate, so the acidity of the residue is a critical factor. Few experimental measurements of the p Ka's of druggable cysteines have been reported, so computational prediction could prove to be very important in selecting reactive cysteine targets. Here we report the computed p Ka's of druggable cysteines in selected protein kinases that are of clinical relevance for targeted therapies. The p Ka's of the cysteines were calculated using advanced computational methods based on all-atom replica-exchange thermodynamic integration molecular dynamics simulations in explicit solvent. We found that the acidities of druggable cysteines within protein kinases are diverse and elevated, indicating enormous differences in their reactivity. Constant-pH molecular dynamics simulations were also performed on selected protein kinases, and the results confirmed this varied range in the acidities of druggable cysteines. Many of these active-site cysteines have low exposure to solvent molecules, elevating their p Ka values. Electrostatic interactions with nearby anionic residues also elevate the p Ka's of cysteine residues in the active site. The results suggest that some cysteine residues within kinase binding sites will be slow to react with a TCI because of their low acidity. Several oncogenic kinase mutations were also modeled and found to have p Ka's similar to that of the wild-type kinase.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Awoonor-Williams E,Rowley CNdoi
10.1021/acs.jcim.8b00454subject
Has Abstractpub_date
2018-09-24 00:00:00pages
1935-1946issue
9eissn
1549-9596issn
1549-960Xjournal_volume
58pub_type
杂志文章abstract：:With the emergence of large collections of protein-ligand complexes complemented by binding data, as found in PDBbind or BindingMOAD, new opportunities for parametrizing and evaluating scoring functions have arisen. With huge data collections available, it becomes feasible to fit scoring functions in a QSAR style, i.e...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci100264e
更新日期：2010-11-22 00:00:00
abstract：:Here, a method is described for easily building three-carbon nanotube junctions. It allows the geometry to be found and bond connectivity of C(3) symmetric nanotube junctions to be established. Such junctions may present a variable degree of pyramidalization and are composed of three identical carbon nanotubes with ar...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200056p
更新日期：2011-06-27 00:00:00
abstract：:Taking into account dynamical behavior and/or structural inaccuracies of receptor-ligand systems becomes increasingly important in structure-based drug design. Here, we describe the development of consensus Adaptation of Fields for Molecular Comparison (AFMoC) (abbreviated as AFMoCcon) models that account for multiple...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci7002472
更新日期：2007-11-01 00:00:00
abstract：:We implemented a fragment-based de novo design algorithm for a population-based optimization of molecular structures. The concept is grounded on an evolution strategy with mutation and crossover operators for structure breeding. Molecular building blocks were obtained from the pseudo-retrosynthesis of a collection of ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci6005307
更新日期：2007-03-01 00:00:00
abstract：:The human cytochrome P450 (CYP450) isozymes are the most important enzymes in the body to metabolize many endogenous and exogenous substances including environmental toxins and therapeutic drugs. Any unnecessary interactions between a small molecule and CYP450 isozymes may raise a potential to disarm the integrity of ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200311w
更新日期：2011-10-24 00:00:00
abstract：:We report the synthesis and a study of the structure-activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate ca...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400189m
更新日期：2013-08-26 00:00:00
abstract：:Dynamical properties of proteins play an essential role in their function exertion. The elastic network model (ENM) is an effective and efficient tool in characterizing the intrinsic dynamical properties encoded in biomacromolecule structures. The Gaussian network model (GNM) and anisotropic network model (ANM) are th...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01178
更新日期：2021-01-26 00:00:00
abstract：:Moving to a new country, with a different culture and a new environment, is not an easy decision. In this perspective, I present some reasons that made me, a Brazilian computational biochemist, move abroad to do postdoctoral research and some of the challenges I faced before and after moving. ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00764
更新日期：2020-02-24 00:00:00
abstract：:Membrane fusion, a key step in the early stages of virus propagation, allows the release of the viral genome in the host cell cytoplasm. The process is initiated by fusion peptides that are small, hydrophobic components of viral membrane-embedded glycoproteins and are typically conserved within virus families. Here, w...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01231
更新日期：2021-01-25 00:00:00
abstract：:A data set of 130 diverse compounds containing both central nervous system (CNS) and non-CNS drugs was used to generate a renal clearance model using a classical Volsurf approach. Percentage renal clearance data was used as a biological input. The score plots obtained from principal component analysis and partial leas...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0503309
更新日期：2006-05-01 00:00:00
abstract：:Deep learning has drawn significant attention in different areas including drug discovery. It has been proposed that it could outperform other machine learning algorithms, especially with big data sets. In the field of pharmaceutical industry, machine learning models are built to understand quantitative structure-acti...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00671
更新日期：2019-03-25 00:00:00
abstract：:Sixteen FDA-approved drugs were investigated to elucidate their mechanisms of action (MOAs) and clinical functions by pathway analysis based on retrieved drug targets interacting with or affected by the investigated drugs. Protein and gene targets and associated pathways were obtained by data-mining of public database...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci4005354
更新日期：2014-02-24 00:00:00
abstract：:The reuptake of neurotransmitters by dopamine, norepinephrine, and serotonin transporters during neuronal transmission requires a sodium gradient. An "ionic mode" of binding proposes that aspartate anchors the ligand's positive charge but ignores the direct role of sodium in ligand binding seen in the only representat...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700255d
更新日期：2008-07-01 00:00:00
abstract：:As an important member of cytochrome P450 (CYP) enzymes, CYP17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones, making it an attractive therapeutic target. The emerging structural information about CYP17A1 and the growing number of inhibitors for these enzymes ca...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00447
更新日期：2020-07-27 00:00:00
abstract：:Characterizing the variability within an ensemble of protein structures is a common requirement in structural biology and bioinformatics. With the increasing number of protein structures becoming available, there is a need for new tools capable of automating the structural comparison of large ensemble of structures. W...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400233j
更新日期：2013-09-23 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：:A compound's synthetic accessibility (SA) is an important aspect of drug design, since in some cases computer-designed compounds cannot be synthesized. There have been several reports on SA prediction, most of which have focused on the difficulties of synthetic reactions based on retro-synthesis analyses, reaction dat...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500568d
更新日期：2014-12-22 00:00:00
abstract：:Protein-ligand (PL) interactions play a key role in many life processes such as molecular recognition, molecular binding, signal transmission, and cell metabolism. Examples of interaction forces include hydrogen bonding, hydrophobic effects, steric clashes, electrostatic contacts, and van der Waals attractions. Curren...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00310
更新日期：2018-01-22 00:00:00
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：:One of the largest commercial applications of enzymes and surfactants is as main components in modern detergents. The high concentration of surfactant compounds usually present in detergents can, however, negatively affect the enzymatic activity. To remedy this drawback, it is of great importance to characterize the i...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00857
更新日期：2019-05-28 00:00:00
abstract：:Given the essential role played by protein kinases in regulating cellular pathways, their dysregulation can result in the onset and/or progression of various human diseases. Structural analysis of diverse protein kinases suggests that these proteins exhibit a remarkable plasticity that allows them to adopt distinct co...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00439
更新日期：2017-10-23 00:00:00
abstract：:Among the photophysical parameters that underpin Förster resonance energy transfer (FRET), perhaps the least explored is the spectral overlap term ( J). While by definition J increases linearly with acceptor molar absorption coefficient (ε(A) in M-1 cm-1), is proportional to wavelength (λ4), and depends on the degree ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00753
更新日期：2019-02-25 00:00:00
abstract：:Glycan Optimized Dual Empirical Spectrum Simulation (GODESS) is a web service, which has been recently shown to be one of the most accurate tools for simulation of (1)H and (13)C 1D NMR spectra of natural carbohydrates and their derivatives. The new version of GODESS supports visualization of the simulated (1)H and (1...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00083
更新日期：2016-06-27 00:00:00
abstract：:A phenotypic screen (PS) is used to identify compounds causing a desired phenotype in a complex biological system where mechanisms and targets are largely unknown. Deconvoluting the mechanism of action of actives and identification of relevant targets and pathways remains a formidable challenge. Current methods fail t...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400245c
更新日期：2014-02-24 00:00:00
abstract：:Large corpora of kinase small molecule inhibitor data are accessible to public sector research from thousands of journal article and patent publications. These data have been generated employing a wide variety of assay methodologies and experimental procedures by numerous laboratories. Here we ask the question how app...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300403k
更新日期：2013-01-28 00:00:00
abstract：:How well do different classification methods perform in selecting the ligands of a protein target out of large compound collections not used to train the model? Support vector machines, random forest, artificial neural networks, k-nearest-neighbor classification with genetic-algorithm-optimized feature selection, tren...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci050519k
更新日期：2006-05-01 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：:Naturally occurring anticancer compounds represent about half of the chemotherapeutic drugs which have been put in the market against cancer until date. Computer-based or in silico virtual screening methods are often used in lead/hit discovery protocols. In this study, the "drug-likeness" of ~400 compounds from Africa...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci5003697
更新日期：2014-09-22 00:00:00
abstract：:The appropriate selection of a chemical space represented by the data set, the selection of its chemical data representation, the development of a correct modeling process using a robust and reproducible algorithm, and the performance of an exhaustive training and external validation determine the usability and reprod...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00492
更新日期：2017-11-27 00:00:00
abstract：:The binding affinity and relative maximal efficacy of human A3 adenosine receptor (AR) agonists were each subjected to ligand-based three-dimensional quantitative structure-activity relationship analysis. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) used a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci600501z
更新日期：2007-05-01 00:00:00
