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::Halogen bonds (XBs) are attracting increasing attention in biological systems. Protein Data Bank (PDB) archives experimentally determined XBs in biological macromolecules. However, no software for structure refinement in X-ray crystallography takes into account XBs, which might result in the weakening or even vanishin...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00235
更新日期:2017-07-24 00:00:00
abstract::Simulating protein flexibility is a major issue in the docking-based drug-design process for which a single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with the challenge of including receptor plasticity in a virtual screening campaign aimed at finding new β-secre...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300390h
更新日期:2012-10-22 00:00:00
abstract::Nitric oxide (NO) is an important signaling molecule produced by a family of enzymes called nitric oxide synthases (NOS). Because NO is involved in various pathological conditions, the development of potent and isoform-selective NOS inhibitors is an important challenge. In the present study, the dimer of oxygenase dom...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100422v
更新日期:2011-06-27 00:00:00
abstract::Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphoshatase (cy-FBP/SBPase) is a potential enzymatic target for screening of novel inhibitors that can combat harmful algal blooms. In the present study, we targeted the substrate binding pocket of cy-FBP/SBPase. A series of novel hit compounds from the SPECs database w...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci4007529
更新日期:2014-03-24 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::Previously, stereoselective hydroxylation of α-ionone by Cytochrome P450 BM3 mutants M01 A82W and M11 L437N was observed. While both mutants hydroxylate α-ionone in a regioselective manner at the C3 position, M01 A82W catalyzes formation of trans-3-OH-α-ionone products whereas M11 L437N exhibits opposite stereoselecti...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300243n
更新日期:2012-08-27 00:00:00
abstract::The SZMAP method computes binding free energies and the corresponding thermodynamic components for water molecules in the binding site of a protein structure [ SZMAP, 1.0.0 ; OpenEye Scientific Software Inc. : Santa Fe, NM, USA , 2011 ]. In this work, the ability of SZMAP to predict water structure and thermodynamic s...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500746d
更新日期:2015-08-24 00:00:00
abstract::Metabolism of xenobiotic and endogenous compounds is frequently complex, not completely elucidated, and therefore often ambiguous. The prediction of sites of metabolism (SoM) can be particularly helpful as a first step toward the identification of metabolites, a process especially relevant to drug discovery. This pape...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400058s
更新日期:2013-06-24 00:00:00
abstract::We describe here our tool named PyPLIF HIPPOS, which was newly developed to analyze the docking results of AutoDock Vina and PLANTS. Its predecessor, PyPLIF (https://github.com/radifar/pyplif), is a molecular interaction fingerprinting tool for the docking results of PLANTS, exclusively. Unlike its predecessor, PyPLIF...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00305
更新日期:2020-08-24 00:00:00
abstract::Determination of structural similarities between protein binding pockets is an important challenge in in silico drug design. It can help to understand selectivity considerations, predict unexpected ligand cross-reactivity, and support the putative annotation of function to orphan proteins. To this end, Cavbase was dev...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci5005898
更新日期:2015-01-26 00:00:00
abstract::Traditionally, a drug potency is expressed in terms of thermodynamic quantities, mostly Kd, and empirical IC50 values. Although binding affinity as an estimate of drug activity remains relevant, it is increasingly clear that it is also important to include (un)binding kinetic parameters in the characterization of pote...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00518
更新日期:2018-11-26 00:00:00
abstract::The spatial sign is a multivariate extension of the concept of sign. Recently multivariate estimators of covariance structures based on spatial signs have been examined by various authors. These new estimators are found to be robust to outlying observations. From a computational point of view, estimators based on spat...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci050498u
更新日期:2006-05-01 00:00:00
abstract::Virtual screening of small molecules against a protein target often identifies the correct pose, but the ranking in terms of binding energy remains a difficult problem, resulting in unacceptable numbers of false positives and negatives. To investigate this problem, the performance of three docking programs, FRED, QXP/...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800154w
更新日期:2008-10-01 00:00:00
abstract::The knowledge of the capacity of a data set to be modeled in the first stages of the building of quantitative structure-activity relationship (QSAR) prediction models is an important issue because it might reduce the effort and time necessary to select or reject data sets and in refining the data set's composition. Th...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00188
更新日期:2018-09-24 00:00:00
abstract::Visualizing high-dimensional data by projecting them into a two- or three-dimensional space is a popular approach in many scientific fields, including computer-aided drug design and cheminformatics. In contrast, dimensionality reduction techniques have been far less explored for materials informatics. Nevertheless, si...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00552
更新日期:2018-12-24 00:00:00
abstract::We report a novel method called ADAN (Applicability Domain ANalysis) for assessing the reliability of drug property predictions obtained by in silico methods. The assessment provided by ADAN is based on the comparison of the query compound with the training set, using six diverse similarity criteria. For every criteri...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500172z
更新日期:2014-05-27 00:00:00
abstract::The three-dimensional structures of 3-anilino-4-arylmaleimides, selective GSK-3beta inhibitors, were correlated to their biological affinities by 3D-QSAR studies (CoMFA method). The cocrystallographic data of GSK-3beta vs 3-anilino-4-arylmaleimide allowed us to compare 3D-QSAR results to experimental intermolecular in...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci050008y
更新日期:2005-05-01 00:00:00
abstract::Knowledge of the interactions between drugs and transporters is important for drug discovery and development as well as for the evaluation of their clinical safety. We recently developed a text-mining system for the automatic extraction of information on chemical-CYP3A4 interactions from the literature. This system is...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci4003188
更新日期:2013-10-28 00:00:00
abstract::Human type II topoisomerases, molecular motors that alter the DNA topology, are a major target of modern chemotherapy. Groups of catalytic inhibitors represent a new approach to overcome the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. Here, we present a class...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00202
更新日期:2020-07-27 00:00:00
abstract::We describe a novel deep learning neural network method and its application to impute assay pIC50 values. Unlike conventional machine learning approaches, this method is trained on sparse bioactivity data as input, typical of that found in public and commercial databases, enabling it to learn directly from correlation...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00768
更新日期:2019-03-25 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::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::In this paper, we introduce the BiKi Life Sciences suite. This software makes it easy for computational medicinal chemists to run ad hoc molecular dynamics protocols in a novel and task-oriented environment; as a notebook, BiKi (acronym of Binding Kinetics) keeps memory of any activity together with dependencies among...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00680
更新日期:2018-02-26 00:00:00
abstract::Congeners are molecules based on the same carbon skeleton but are different by the number of substituents and/or a substitution pattern. Examples are 1-chloronaphthalene, 1,4-dichloronaphthalene, and 1,3,8-trichloronaphthalene. Various persistent organic pollutants (POPs) exist in the environment as families of congen...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300289b
更新日期:2012-11-26 00:00:00
abstract::In structure-based drug design, scoring functions are often employed to evaluate protein-ligand interactions. A variety of scoring functions have been developed so far, and thus, some objective benchmarks are desired for assessing their strength and weakness. The comparative assessment of scoring functions (CASF) benc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00545
更新日期:2019-02-25 00:00:00
abstract::The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci3003914
更新日期:2013-01-28 00:00:00
abstract::Histone deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases, and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective histone deacetylase inhibitors (HDACIs). To facilitat...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci5005515
更新日期:2015-02-23 00:00:00
abstract::We propose an improved solvent contact model to estimate the solvation free energy of an organic molecule from individual atomic contributions. The modification of the solvation model involves the optimization of three kinds of parameters in the solvation free energy function: atomic fragmental volume, maximum atomic ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci600453b
更新日期:2007-03-01 00:00:00
abstract::Three-dimensional protein structures are a key requisite for structure-based drug discovery. For many highly relevant targets, medicinal chemists are confronted with large numbers of target structures in their apo-forms or in complex with a wealth of different ligands. To exploit the full potential of such structure e...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00051
更新日期:2020-04-27 00:00:00
abstract::The programs Phase and Catalyst HypoGen are compared for their performance in determining three-dimensional quantitative structure-activity relationships. Eight sets of compounds with measured activity were collected from the public literature and partitioned into suitable training and test sets by an automated proced...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci7000082
更新日期:2007-05-01 00:00:00