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 ensembles, in terms of aggregated knowledge that informs design, it is desirable to extract a manageable number of structures that provide a maximum of ligand design opportunities. Most commonly used structure comparison methods are largely based on atom positions and geometry-based metrics; medicinal chemists, however, seek ligand design opportunities and are interested in methods that allow such information to be distilled from structural data and guide them in an intuitive way. Here we present an approach for identifying nonobvious ligand design opportunities in protein conformation ensembles based on the information content in grid maps that represent, for example, binding hotspots. We use four different examples to show how this method can provide information orthogonal to established coordinate-based similarity methods. Furthermore, we demonstrate that ligand design opportunities can change substantially with very small structural variations. We expect that this approach will advance the identification of ligand design opportunities hidden in large collections of protein-ligand complex data that would otherwise have been missed.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Schmalhorst PS,Bergner Adoi
10.1021/acs.jcim.0c00051subject
Has Abstractpub_date
2020-04-27 00:00:00pages
2178-2188issue
4eissn
1549-9596issn
1549-960Xjournal_volume
60pub_type
杂志文章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::In this DFT study, activities of 11 different N2O4, N2O3, and NO2 core containing Zr(IV) complexes, 4,13-diaza-18-crown-6 (I'N2O4), 1,4,10-trioxa-7,13-diazacyclopentadecane (I'N2O3), and 2-(2-methoxy)ethanol (I'NO2), respectively, and their analogues in peptide hydrolysis have been investigated. Based on the experimen...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00781
更新日期:2017-05-22 00:00:00
abstract::The predictive performances of MC4PC were evaluated using its learning machine functionality. Its superior characteristics are demonstrated in this following up study using the newly published Ames mutagenicity benchmark set. ...
journal_title:Journal of chemical information and modeling
pub_type: 评论,信件
doi:10.1021/ci1000899
更新日期:2010-09-27 00:00:00
abstract::Molecular fingerprints are widely used for similarity-based virtual screening in drug discovery projects. In this paper we discuss the performance and the complementarity of nine two-dimensional fingerprints (Daylight, Unity, AlFi, Hologram, CATS, TRUST, Molprint 2D, ChemGPS, and ALOGP) in retrieving active molecules ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci0504723
更新日期:2006-05-01 00:00:00
abstract::We have performed a ligand coordinate analysis to monitor the movement of the inhibitor SC-558 from the active site of the COX-2 protein to the exterior using molecular dynamics techniques. This study provides an insight into the intermolecular interactions formed by the ligand during this journey. The published cryst...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci050142i
更新日期:2006-07-01 00:00:00
abstract::Up to now, publicly available data sets to build and evaluate Ames mutagenicity prediction tools have been very limited in terms of size and chemical space covered. In this report we describe a new unique public Ames mutagenicity data set comprising about 6500 nonconfidential compounds (available as SMILES strings and...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci900161g
更新日期:2009-09-01 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::To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercial...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci900068k
更新日期:2009-05-01 00:00:00
abstract::Resonance structures of polycyclic aromatic hydrocarbons can be associated with numerical formulas by assigning pi-electrons of C=C double bonds to individual benzenoid rings. Each C=C double bond in a resonance structure assigns two pi-electrons to a ring in a fused-benzenoid system if it is not shared by adjacent ri...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci050196s
更新日期:2006-01-01 00:00:00
abstract::The partitioning of solute molecules between immiscible solvents with significantly different polarities is of great importance. The polarization between the solute and solvent molecules plays an essential role in determining the solubility of the solute, which makes computational studies utilizing molecular mechanics...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00001
更新日期:2017-10-23 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::We have performed a systematic study of the entropy term in the MM/GBSA (molecular mechanics combined with generalized Born and surface-area solvation) approach to calculate ligand-binding affinities. The entropies are calculated by a normal-mode analysis of harmonic frequencies from minimized snapshots of molecular d...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci3001919
更新日期:2012-08-27 00:00:00
abstract::A generic chemical transformation may often be achieved under various synthetic conditions. However, for any specific reagents, only one or a few among the reported synthetic protocols may be successful. For example, Michael β-addition reactions may proceed under different choices of solvent (e.g., hydrophobic, aproti...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500698a
更新日期:2015-02-23 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::Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00336
更新日期:2015-12-28 00:00:00
abstract::Mapping the chemical space of small organic molecules is approached from a theoretical graph theory viewpoint, in an effort to begin the systematic exploration of molecular topologies. We present an algorithm for exhaustive generation of scaffold topologies with up to eight rings and an efficient comparison method for...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci7003412
更新日期:2008-07-01 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::We introduce TICRA (transplant-insert-constrain-relax-assemble), a method for modeling the structure of unknown protein-ligand complexes using the X-ray crystal structures of homologous proteins and ligands with known activity. We present results from modeling the structures of protein kinase-inhibitor complexes using...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100256u
更新日期:2011-01-24 00:00:00
abstract::With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of μ- and δ-opioid receptor types have been re...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00388
更新日期:2015-09-28 00:00:00
abstract::Proteins often have both orthosteric and allosteric binding sites. Endogenous ligands, such as hormones and neurotransmitters, bind to the orthosteric site, while synthetic ligands may bind to orthosteric or allosteric sites, which has become a focal point in drug discovery. Usually, such allosteric modulators bind to...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00695
更新日期:2020-10-26 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::Calcium and magnesium ions play important roles in many physicochemical processes. To facilitate the investigation of phenomena related to these ions that occur over large length and time scales, a coarse-grained force field (CGFF) is developed for MgCl2 and CaCl2 aqueous solutions. The ions are modeled by CG beads wi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00206
更新日期:2017-07-24 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::Many of the conventional similarity methods assume that molecular fragments that do not relate to biological activity carry the same weight as the important ones. One possible approach to this problem is to use the Bayesian inference network (BIN), which models molecules and reference structures as probabilistic infer...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100232h
更新日期:2011-01-24 00:00:00
abstract::A new methodology to describe the interactions in "receptor-ligand" complexes is presented. The methodology is based on a combination of the 3D/4D QSAR BiS/MC and CoCon algorithms. The first algorithm performs the restricted docking of compounds to receptor pockets. The second determines the relationships between the ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800405n
更新日期:2009-06-01 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::CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700313e
更新日期:2008-01-01 00:00:00
abstract::An important issue in developing protein-ligand docking methods is how to incorporate receptor flexibility. Consideration of receptor flexibility using an ensemble of precompiled receptor conformations or by employing an effectively enlarged binding pocket has been reported to be useful. However, direct consideration ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300342z
更新日期:2012-12-21 00:00:00
abstract::Development of coarse-grained (CG) molecular dynamics models is often a laborious process which commonly relies upon approximations to similar models, rather than systematic parametrization. PyCGTOOL automates much of the construction of CG models via calculation of both equilibrium values and force constants of inter...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00096
更新日期:2017-04-24 00:00:00
abstract::With a rapid increase in the number of high-resolution protein-ligand structures, the known protein-ligand structures can be used to gain insight into ligand-binding modes in a target protein. On the basis of the fact that the structurally similar binding sites share information about their ligands, we have developed ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300178e
更新日期:2012-10-22 00:00:00