Abstract:
:As computational drug design becomes increasingly reliant on virtual screening and on high-throughput 3D modeling, the need for fast, robust, and reliable methods for sampling molecular conformations has become greater than ever. Furthermore, chemical novelty is at a premium, forcing medicinal chemists to explore more complex structural motifs and unusual topologies. This necessitates the use of conformational sampling techniques that work well in all cases. Here, we compare the performance of several popular conformational search algorithms on three broad classes of macrocyclic molecules. These methods include Catalyst, CAESAR, MacroModel, MOE, Omega, Rubicon and two newer self-organizing algorithms known as stochastic proximity embedding (SPE) and self-organizing superimposition (SOS) that have been developed at Johnson & Johnson. Our results show a compelling advantage for the three distance geometry methods (SOS, SPE, and Rubicon) followed to a lesser extent by MacroModel. The remaining techniques, particularly those based on systematic search, often failed to identify any of the lowest energy conformations and are unsuitable for this class of structures. Taken together with our previous study on drug-like molecules (Agrafiotis, D. K.; Gibbs, A.; Zhu, F.; Izrailev, S.; Martin, E. Conformational Sampling of Bioactive Molecules: A Comparative Study. J. Chem. Inf. Model., 2007, 47, 1067-1086), these results suggest that SPE and SOS are two of the most robust and universally applicable conformational search methods, with the latter being preferred because of its superior speed.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Bonnet P,Agrafiotis DK,Zhu F,Martin Edoi
10.1021/ci900238asubject
Has Abstractpub_date
2009-10-01 00:00:00pages
2242-59issue
10eissn
1549-9596issn
1549-960Xjournal_volume
49pub_type
杂志文章abstract::Protein-polysaccharide complexes constructed via self-assembly methods are often used to develop novel biomaterials for a wide range of applications in biomedicine, food, and biotechnology. The objective of this work was to investigate theoretically and to demonstrate via constant-pH Monte Carlo simulations that the c...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00814
更新日期:2020-02-24 00:00:00
abstract::We have applied the two most commonly used methods for automatic matched pair identification, obtained the optimum settings, and discovered that the two methods are synergistic. A turbocharging approach to matched pair analysis is advocated in which a first round (a conservative categorical approach that uses an analo...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00335
更新日期:2017-10-23 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::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::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 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::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::Identifying sequence modifications that distinguish psychrophilic from mesophilic proteins is important for designing enzymes with different thermodynamic stabilities and to understand the underlying mechanisms. The PoPMuSiC algorithm is used to introduce, in silico, all the single-site mutations in four mesophilic an...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci050473v
更新日期:2006-05-01 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::Aminoglycosides are antibiotics targeting the 16S RNA A site of the bacterial ribosome. There have been many efforts directed toward design of their synthetic derivatives, however with only few successes. As RNA binders, aminoglycosides are also a difficult target for computational drug design, since most of the exist...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800361a
更新日期:2009-02-01 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::Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein-protein binding sites. The algorithms use maximum cliques on protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100265x
更新日期:2010-10-25 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::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::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::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::The prediction of protein-ligand binding affinity has recently been improved remarkably by machine-learning-based scoring functions. For example, using a set of simple descriptors representing the atomic distance counts, the RF-Score improves the Pearson correlation coefficient to about 0.8 on the core set of the PDBb...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00049
更新日期:2017-04-24 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::Acetohydroxyacid synthase (AHAS) is a thiamin diphosphate-dependent enzyme involved in the biosynthesis of valine, leucine, isoleucine, and lysine. Experimental evidence has shown that mutation of the Gln202 residue results in a decrease in the enzymatic activity, thus suggesting the main role of the carboligation cat...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00863
更新日期:2020-02-24 00:00:00
abstract::The accurate prediction of the adsorption energies of unsaturated molecules on graphene in the presence of water is essential for the design of molecules that can modify its properties and that can aid its processability. We here show that a semiempirical MO method corrected for dispersive interactions (PM6-DH2) can p...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci5003729
更新日期:2014-08-25 00:00:00
abstract::Accurate hydrogen placement in molecular modeling is crucial for studying the interactions and dynamics of biomolecular systems. The carboxyl functional group is a prototypical example of a functional group that requires protonation during structure preparation. To our knowledge, when in their neutral form, carboxylic...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00835
更新日期:2019-05-28 00:00:00
abstract::Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-bindi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci2000055
更新日期:2011-05-23 00:00:00
abstract::Water is the natural medium of molecules in the cell and plays an important role in protein structure, function and interaction with small molecule ligands. However, the widely used molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method for binding energy calculation does not explicitly take account of wa...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci4001794
更新日期:2014-02-24 00:00:00
abstract::The primary goal of this project was to evaluate the performance of the Standard and Enforced Geometry Optimization (SEGO) method which we have recently developed. The SEGO method has been designed for an automatic location of multiple minima on the molecular Potential Energy Surface (PES), and its usefulness has been...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00352
更新日期:2019-08-26 00:00:00
abstract::The important role of water molecules in protein-ligand binding energetics has attracted wide attention in recent years. A range of computational methods has been developed to predict the favorable locations of water molecules in a protein binding pocket. Most of the current methods are based on extensive molecular dy...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00619
更新日期:2020-09-28 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::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::The present study focuses on the determination of the biologically significant N-acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human α-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectrosc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00558
更新日期:2019-01-28 00:00:00