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 prediction approaches on bigger datasets. We present a prediction method for binding kinetics based on the machine learning analysis of protein-ligand structural features, which can serve as a baseline for more sophisticated methods utilizing molecular dynamics (MD). We showed that the random forest algorithm is capable of learning the protein binding site secondary structure and backbone/side-chain features to predict the binding kinetics of protein-ligand complexes but still with inferior performance to that of MD-based descriptor analysis. MD simulations had been applied to a limited number of targets and a series of ligands in terms of kinetics analysis, and we believe that the developed approach may guide new studies. The method was trained on a newly curated database of 501 protein-ligand unbinding rate constants, which can also be used for testing and training the binding kinetics prediction models.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Amangeldiuly N,Karlov D,Fedorov MVdoi
10.1021/acs.jcim.0c00450subject
Has Abstractpub_date
2020-12-28 00:00:00pages
5946-5956issue
12eissn
1549-9596issn
1549-960Xjournal_volume
60pub_type
杂志文章abstract：:Big data is one of the key transformative factors which increasingly influences all aspects of modern life. Although this transformation brings vast opportunities it also generates novel challenges, not the least of which is organizing and searching this data deluge. The field of medicinal chemistry is not different: ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00249
更新日期：2017-08-28 00:00:00
abstract：:We propose a hypothesis that "a model of active compound can be provided by integrating information of compounds high-ranked by docking simulation of a random compound library". In our hypothesis, the inclusion of true active compounds in the high-ranked compound is not necessary. We regard the high-ranked compounds a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci7003384
更新日期：2008-03-01 00:00:00
abstract：:A machine learning enhanced spectrum recognition system called spectrum recognition based on computer vision (SRCV) for data extraction from previously analyzed 13C and 1H NMR spectra has been developed. The intelligent system was designed with four function modules to extract data from three areas of NMR images, incl...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01046
更新日期：2021-01-25 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：:The enzyme UDP-galactopyranose mutase (UGM) represents a promising drug target for the treatment of infections with Trypanosoma cruzi. We have computed the Potential of Mean Force for the release of UDP-galactopyranose from UGM, using Umbrella Sampling simulations. The simulations revealed the conformational changes t...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00675
更新日期：2019-02-25 00:00:00
abstract：:Partial covalent interactions (PCIs) in proteins, which include hydrogen bonds, salt bridges, cation-π, and π-π interactions, contribute to thermodynamic stability and facilitate interactions with other biomolecules. Several score functions have been developed within the Rosetta protein modeling framework that identif...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00398
更新日期：2018-05-29 00:00:00
abstract：:Theoretical calculation of equilibrium dissociation constants is a very computationally demanding and time-consuming process since it requires an extremely accurate computation of the solvation free energy changes for each of the species involved. By correlating the minimum surface electrostatic potential (VS,min) on ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b01173
更新日期：2020-03-23 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：: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：: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：:Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are u...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00581
更新日期：2016-01-25 00:00:00
abstract：:The importance of thorough analyses of the secondary structures in proteins as basic structural units cannot be overemphasized. Although recent computational methods have achieved reasonably high accuracy for predicting secondary structures from amino acid sequences, a simple and fundamental empirical approach to char...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci900452z
更新日期：2010-04-26 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：:Discovery of new antibacterial agents is a never-ending task of medicinal chemistry. Every new drug brings significant improvement to patients with bacterial infections, but prolonged usage of antibacterials leads to the emergence of resistant strains. Therefore, novel active structures with new modes of action are re...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00436
更新日期：2019-11-25 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：:The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we p...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00336
更新日期：2017-10-23 00:00:00
abstract：:A giant technological leap in the field of cryo-electron microscopy (cryo-EM) has assured the achievement of near-atomic resolution structures of biological macromolecules. As a recognition of this accomplishment, the Nobel Prize in Chemistry was awarded in 2017 to Jacques Dubochet, Joachim Frank, and Richard Henderso...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b01015
更新日期：2020-05-26 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：: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 antiproliferative factor (APF) involved in interstitial cystitis is a glycosylated nonapeptide (TVPAAVVVA) containing a sialylated core 1 α-O-disaccharide linked to the N-terminal threonine. The chemical structure of APF was deduced using spectroscopic techniques and confirmed using total synthesis. The synthetic ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400147s
更新日期：2013-05-24 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：: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：:The causative agent of African sleeping sickness, Trypanosoma brucei , undergoes an unusual mitochondrial RNA editing process that is essential for its survival. RNA editing terminal uridylyl transferase 2 of T. brucei (TbRET2) is an indispensable component of the editosome machinery that performs this editing. TbR...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci3001327
更新日期：2012-05-25 00:00:00
abstract：:We have developed a computer program for molecular dynamics (MD) simulation that implements the Split Integration Symplectic Method (SISM) and is designed to run on specialized parallel computers. The MD integration is performed by the SISM, which analytically treats high-frequency vibrational motion and thus enables ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci050216q
更新日期：2005-11-01 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：:Reaction databases provide a great deal of useful information to assist planning of experiments but do not provide any interpretation or chemical concepts to accompany this information. In this work, reactions are labeled with experimental conditions, and network analysis shows that consistencies within clusters of da...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00313
更新日期：2019-09-23 00:00:00
abstract：:The goal of the present study was to ascertain the differential performance of a long molecular dynamics trajectory versus several shorter ones starting from different points in the phase space and covering the same sampling time. For this purpose, we selected the 16-mer peptide Bak16BH3 as a model for study and carri...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00347
更新日期：2016-10-24 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：: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：:We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300604z
更新日期：2013-08-26 00:00:00
