Abstract：
:It is demonstrated that the fragmentation of druglike molecules by applying simplistic pseudo-retrosynthesis results in a stock of chemically meaningful building blocks for de novo molecule generation. A stochastic search algorithm in conjunction with ligand-based similarity scoring (Flux: fragment-based ligand builder reaxions) facilitated the generation of new molecules using a single known reference compound as a template. This molecule assembly method is applicable in the absence of receptor-structure information. In a case study, we used imantinib (Gleevec) and a Factor Xa inhibitor as the reference structures. The algorithm succeeded in redesigning the templates from scratch and suggested several alternative molecular structures. The resulting designed molecules were chemically reasonable and contained essential substructure motifs. A comparison of molecular descriptors suggests that holographic descriptors might be advantageous over binary fingerprints for ligand-based de novo design.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Fechner U,Schneider Gdoi
10.1021/ci0503560keywords:
subject
Has Abstractpub_date
2006-03-01 00:00:00pages
699-707issue
2eissn
1549-9596issn
1549-960Xjournal_volume
46pub_type
杂志文章abstract：:Retrieving molecules with specific structural features is a fundamental requirement of today's molecular database technologies. Estimates claim the chemical space relevant for drug discovery to be around 10⁶⁰ molecules. This figure is many orders of magnitude larger than the amount of molecules conventional databases ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400107k
更新日期：2013-07-22 00:00:00
abstract：:Factor Xa inhibitors are innovative anticoagulant agents that provide a better safety/efficacy profile compared to other anticoagulative drugs. A chemical feature-based modeling approach was applied to identify crucial pharmacophore patterns from 3D crystal structures of inhibitors bound to human factor Xa (Pdb entrie...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci049778k
更新日期：2005-01-01 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：:Thermoplastic polyurethanes (TPUs) are designed using a large variety of basic building blocks but are only synthesized in a limited number of solvent systems. Understanding the behavior of the copolymers in a selected solvent system is of particular interest to tune the intricate balance of microphase separation/mixi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00781
更新日期：2019-05-28 00:00:00
abstract：:Methods that rapidly evaluate molecular complexity and synthetic feasibility are becoming increasingly important for in silico chemistry. We propose a new metric based on relative atomic electronegativities and bond parameters that evaluate both synthetic and molecular complexity (SMCM) starting from chemical structur...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0501387
更新日期：2005-09-01 00:00:00
abstract：:The α2a adrenoceptor is a medically relevant subtype of the G protein-coupled receptor family. Unfortunately, high-throughput techniques aimed at producing novel drug leads for this receptor have been largely unsuccessful because of the complex pharmacology of adrenergic receptors. As such, cutting-edge in silico liga...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c01019
更新日期：2021-01-25 00:00:00
abstract：:Alanine scanning is a tool in molecular biology that is commonly used to evaluate the contribution of a specific amino acid residue to the stability and function of a protein. Additionally, this tool is also used to understand whether the side chain of a specific amino acid residue plays a role in the protein's bioact...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00926
更新日期：2019-02-25 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：:A new structure classification scheme for biopolymers is introduced, which is solely based on main-chain dihedral angles. It is shown that by dividing a biopolymer into segments containing two central residues, a local classification can be performed. The method is referred to as DISICL, short for Dihedral-based Segme...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400541d
更新日期：2014-01-27 00:00:00
abstract：:An in silico screening procedure was performed to select new inhibitors of glycogen synthase kinase 3β (GSK-3β), a serine/threonine protein kinase that in the last two decades has emerged as a key target in drug discovery, having been implicated in multiple cellular processes and linked with the pathogenesis of severa...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00486
更新日期：2015-12-28 00:00:00
abstract：:As a key player in cell adhesion, the glycoprotein fibronectin is involved in the complex mechanobiology of the extracellular matrix. Although the function of many modules in the fibronectin molecule has already been understood, the structure and biological relevance of the C-terminal cross-linked region (CTXL) still ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00555
更新日期：2019-10-28 00:00:00
abstract：:Cryo-electron microscopy (cryo-EM) is emerging as a real alternative for structural elucidation. In spite of this, very few cryo-EM structures have been described so far as successful platforms for in silico drug design. Gabapentin and pregabalin are some of the most successful drugs in the treatment of epilepsy and n...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.8b00347
更新日期：2018-08-27 00:00:00
abstract：:Solubility parameter models are widely used to select suitable solvents/nonsolvents for polymers in a variety of processing and engineering applications. In this study, we focus on two well-established models, namely, the Hildebrand and Hansen solubility parameter models. Both models are built on the basis of the noti...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00656
更新日期：2019-10-28 00:00:00
abstract：:With chemical libraries increasingly containing millions of compounds or more, there is a fast-growing need for computational methods that can rank or prioritize compounds for screening. Machine learning methods have shown considerable promise for this task; indeed, classification methods such as support vector machin...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci9003865
更新日期：2010-05-24 00:00:00
abstract：:Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In thi...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00763
更新日期：2017-06-26 00:00:00
abstract：:This article presents the computation of both inter- and intramolecular hydrogen bond strengths from first-principles. Quantum chemical calculations conducted at the dispersion-corrected density functional theory level including free energy and solvation contributions are conducted for (i) one-to-one hydrogen-bonded c...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00132
更新日期：2019-09-23 00:00:00
abstract：:Virtual screening (VS) can be accomplished in either ligand- or structure-based methods. In recent times, an increasing number of 2D fingerprint and 3D shape similarity methods have been used in ligand-based VS. To evaluate the performance of these ligand-based methods, retrospective VS was performed on a tailored dir...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci300030u
更新日期：2012-05-25 00:00:00
abstract：:The recent article "Evaluation of pK(a) Estimation Methods on 211 Druglike Compounds" ( Manchester, J.; et al. J. Chem Inf. Model. 2010, 50, 565-571 ) reports poor results for the program Epik. Here, we highlight likely sources for the poor performance and describe work done to improve the performance. Running Epik in...
journal_title：Journal of chemical information and modeling
pub_type： 评论,杂志文章
doi：10.1021/ci100332m
更新日期：2011-01-24 00:00:00
abstract：:In the present work, the Henderson-Hasselbalch (HH) equation has been employed for the development of a tool for the prediction of pH-dependent aqueous solubility of drugs and drug candidates. A new prediction method for the intrinsic solubility was developed, based on artificial neural networks that have been trained...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci600292q
更新日期：2006-11-01 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：: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：:Estrogens exert important physiological effects through the modulation of two human estrogen receptor (hER) subtypes, alpha (hERalpha) and beta (hERbeta). Because the levels and relative proportion of hERalpha and hERbeta differ significantly in different target cells, selective hER ligands could target specific tissu...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci8002182
更新日期：2008-11-01 00:00:00
abstract：:We used synthetic peloruside A for the commercial preparation of [³H]peloruside A. The radiolabeled compound bound to preformed tubulin polymer in amounts stoichiometric with the polymer's tubulin content, with an apparent K(d) value of 0.35 μM. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci1002894
更新日期：2010-11-22 00:00:00
abstract：:3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relatio...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci800147v
更新日期：2008-09-01 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：:CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400225w
更新日期：2013-08-26 00:00:00
abstract：:An essential feature of all practical de novo molecule generating programs is the ability to focus the potential combinatorial explosion of grown molecules on a desired chemical space. It is a daunting task to balance the generation of new molecules with limitations on growth that produce desired features such as stab...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci9000458
更新日期：2009-07-01 00:00:00
abstract：:The anatomical therapeutic chemical (ATC) classification system maintained by the World Health Organization provides a global standard for the classification of medical substances and serves as a source for drug repurposing research. Nevertheless, it lacks several drugs that are major players in the global drug market...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci9000844
更新日期：2009-08-01 00:00:00
abstract：:Deep learning has demonstrated significant potential in advancing state of the art in many problem domains, especially those benefiting from automated feature extraction. Yet, the methodology has seen limited adoption in the field of ligand-based virtual screening (LBVS) as traditional approaches typically require lar...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00622
更新日期：2020-10-26 00:00:00
abstract：:The effects of paclitaxel (PTX) loading fraction and spatial PTX arrangement on poly(γ-glutamyl-glutamate) paclitaxel (PGG-PTX) aggregation were explored using coarse-grained molecular dynamics. Results show that the PTX loading fraction does not significantly impact aggregation, and the spatial PTX arrangement only a...
journal_title：Journal of chemical information and modeling
pub_type： 信件
doi：10.1021/ci200214m
更新日期：2011-12-27 00:00:00
