Abstract：
:Inhibition of protein-protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy--that builds on the principles of fragment-based drug discovery (FBDD)--is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein's Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features--alpha-atom and alpha-space--and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Rooklin D,Wang C,Katigbak J,Arora PS,Zhang Ydoi
10.1021/acs.jcim.5b00103subject
Has Abstractpub_date
2015-08-24 00:00:00pages
1585-99issue
8eissn
1549-9596issn
1549-960Xjournal_volume
55pub_type
杂志文章abstract：:Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descr...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500276x
更新日期：2014-08-25 00:00:00
abstract：:Several drugs elicit their therapeutic efficacy by modulating multiple cellular targets and possess varied polypharmacological actions. The identification of the molecular targets of a potent bioactive molecule is essential in determining its overall polypharmacological profile. Experimental procedures are expensive a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00227
更新日期：2018-01-22 00:00:00
abstract：:Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and in both immunodeficient and immunocompetent patients. 1,8-Dihydroxynaphthalene-melanin is found in the cell wall of C. lunata and is believed to be the important virulence factor of dematiaceous fungi. Trihydroxy...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci2001499
更新日期：2011-07-25 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：:Saturated acyclic alkanes show steric strain if they are highly branched and, in extreme cases, fall apart rapidly at room temperature. Consequently, attempts to count the number of isomeric forms for a given molecular formula that neglect this physical consideration will inevitably overestimate the size of the availa...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700246b
更新日期：2007-11-01 00:00:00
abstract：:Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, onl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500001f
更新日期：2014-06-23 00:00:00
abstract：:Mass spectrometric data are copious and generate a processing burden that is best dealt with programmatically. PythoMS is a collection of tools based on the Python programming language that assist researchers in creating figures and video output that is informative, clear, and visually compelling. The PythoMS framewor...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00055
更新日期：2019-04-22 00:00:00
abstract：:The solvation layer surrounding a protein is clearly an intrinsic part of protein structure-dynamics-function, and our understanding of how the hydration dynamics influences protein function is emerging. We have recently reported simulations indicating a correlation between regional hydration dynamics and the structur...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00009
更新日期：2019-05-28 00:00:00
abstract：:The human cytochrome P450 1A2 is an important drug metabolizing and procarcinogen activating enzyme. An experimental study found that a peripheral mutation, F186L, at ∼26 Å away from the enzyme's active site, caused a significant reduction in the enzymatic activity of 1A2 deethylation reactions. In this paper, we expl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200112b
更新日期：2011-06-27 00:00:00
abstract：:There is a renewed interest in computer-aided synthesis planning, where the vast majority of approaches require the application of retrosynthetic reaction templates. Here we introduce RDChiral, an open-source Python wrapper for RDKit designed to provide consistent handling of stereochemical information in applying ret...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00286
更新日期：2019-06-24 00:00:00
abstract：:Standardization is used to ensure that the variables in a similarity calculation make an equal contribution to the computed similarity value. This paper compares the use of seven different methods that have been suggested previously for the standardization of integer-valued or real-valued data, comparing the results w...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci800224h
更新日期：2009-02-01 00:00:00
abstract：:Aβ25-35 is a short, cytotoxic, and naturally occurring fragment of the Alzheimer's Aβ peptide. To map the molecular mechanism of Aβ25-35 binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer, we have performed replica exchange with solute tempering molecular dynamics simulations using all-atom expl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00045
更新日期：2018-05-29 00:00:00
abstract：:A comprehensive safety evaluation of chemicals should require toxicity assessment in both the aquatic and terrestrial test species. Due to the application practices and nature of chemical pesticides, the avian toxicity testing is considered as an essential requirement in the risk assessment process. In this study, tre...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00139
更新日期：2015-07-27 00:00:00
abstract：:We present an induced fit docking approach called Adaptive BP-Dock that integrates perturbation response scanning (PRS) with the flexible docking protocol of RosettaLigand in an adaptive manner. We first perturb the binding pocket residues of a receptor and obtain a new conformation based on the residue response fluct...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00587
更新日期：2016-04-25 00:00:00
abstract：:TAMkin is a program for the calculation and analysis of normal modes, thermochemical properties and chemical reaction rates. At present, the output from the frequently applied software programs ADF, CHARMM, CPMD, CP2K, Gaussian, Q-Chem, and VASP can be analyzed. The normal-mode analysis can be performed using a broad ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci100099g
更新日期：2010-09-27 00:00:00
abstract：:Cathepsin A is a mammalian lysosomal enzyme that catalyzes the hydrolysis of the carboxy-terminal amino acids of polypeptides and also regulates beta-galactosidase and neuraminidase-1 activities through the formation of a multienzymic complex in lysosomes. Human cathepsin A (hCathA), yeast carboxypeptidase (CPY), and ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci060093p
更新日期：2006-09-01 00:00:00
abstract：:Various cages are constructed by using three types of caps: f-cap (derived from spherical fullerenes by deleting zones of various size), kf-cap (obtainable by cutting off the polar ring, of size k), and t-cap ("tubercule"-cap). Building ways are presented, some of them being possible isomerization routes in the real c...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci049738g
更新日期：2005-03-01 00:00:00
abstract：:Target-oriented substructure-based virtual screening (sSBVS) of molecules is a promising approach in drug discovery. Yet, there are doubts whether sSBVS is suitable also for extrapolation, that is, for detecting molecules that are very different from those used for training. Herein, we evaluate the predictive power of...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci200472s
更新日期：2012-03-26 00:00:00
abstract：:Due to the importance of hot-spots (HS) detection and the efficiency of computational methodologies, several HS detecting approaches have been developed. The current paper presents new models to predict HS for protein-protein and protein-nucleic acid interactions with better statistics compared with the ones currently...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500760m
更新日期：2015-05-26 00:00:00
abstract：:Derivation of structure-kinetics relationships can help rational design and development of new small-molecule drug candidates with desired residence times. Efforts are now being directed toward the development of efficient computational methods. Currently, there is a lack of solid, high-throughput binding kinetics pre...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00450
更新日期：2020-12-28 00:00:00
abstract：:Reduction of the affinity of the fragment crystallizable (Fc) region with immune receptors by substitution of one or a few amino acids, known as Fc-silencing, is an established approach to reduce the immune effector functions of monoclonal antibody therapeutics. This approach to Fc-silencing, however, is problematic a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b01198
更新日期：2020-11-23 00:00:00
abstract：:A kinetic, reactivity-binding model has been proposed to predict the regioselectivity of substrates meditated by the CYP1A2 enzyme, which is responsible for the metabolism of planar-conjugated compounds such as caffeine. This model consists of a docking simulation for binding energy and a semiempirical molecular orbit...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci800001m
更新日期：2008-05-01 00:00:00
abstract：:Fragment complementation is gaining an increasing impact as a nonperturbing method to probe noncovalent interactions within protein supersecondary structures. In this study, the fast Fourier transform rigid-body docking algorithm ZDOCK has been employed for in silico reconstitution of the calcium binding protein calbi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0501995
更新日期：2005-09-01 00:00:00
abstract：:Maltose-binding protein is a periplasmic binding protein responsible for transport of maltooligosaccarides through the periplasmic space of Gram-negative bacteria, as a part of the ABC transport system. The molecular mechanisms of the initial ligand binding and induced large scale motion of the protein's domains still...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci500520q
更新日期：2015-02-23 00:00:00
abstract：:In this study, we have developed a two model system to mimic the active and inactive states of a G-protein coupled receptor specifically the alpha1A adrenergic receptor. We have docked two agonists, epinephrine (phenylamine type) and oxymetazoline (imidazoline type), as well as two antagonists, prazosin and 5-methylur...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700026v
更新日期：2007-09-01 00:00:00
abstract：:Due to the recent availability of high quality small molecule databases, such as ZINC and PubChem,1,2 virtual screening is playing an even more important role in identifying biologically relevant molecules in drug discovery campaigns. The success of pharmacophore-based virtual screening (PBVS) relies largely on the ac...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci700089w
更新日期：2007-07-01 00:00:00
abstract：:Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the G-quadruplex have great potential to be developed as anticancer agents. Two crystal structures (an apo form of parallel stranded human telomeric G-quadruplex and its h...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00287
更新日期：2017-11-27 00:00:00
abstract：:Although there are several databases that contain data on many metabolites and reactions in biochemical pathways, there is still a big gap in the numbers between experimentally identified enzymes and metabolites. It is supposed that many catalytic enzyme genes are still unknown. Although there are previous studies tha...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00216
更新日期：2016-03-28 00:00:00
abstract：:Insect neuropeptide receptors, including allatostatin receptor type C (AstR-C), a G protein-coupled receptor, are among the potential targets for designing next-generation pesticides that despite their importance in offering a new mode-of-action have been overlooked. Focusing on AstR-C of Thaumetopoea pityocampa, a co...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00985
更新日期：2021-01-21 00:00:00
abstract：:While critically reviewing the current status of what is known about C28H14 and C30H14 benzenoid isomers, which are ubiquitous pyrolytic constituents, some new insights will be presented. Representative isomers belonging to these benzenoid hydrocarbons are at the crossroads to homologous series that extend to infinite...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci050298i
更新日期：2006-03-01 00:00:00
