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 a potential target to discover drugs fighting against the invasive diseases originated from S. pneumoniae . However, no significantly effective inhibitors of class II HMGR have been reported so far. In the present study, the reasonable three-dimensional (3D) structure of class II HMGR from S. pneumoniae (SP-HMGR-II) was built by Swissmodel. On the basis of the modeling 3D structure in "close" flap domain form, several novel potential hit compounds out of SPECs database were picked out by using structure-based screening strategy. Especially the compounds 4, 3, and 11 exhibit highly inhibitory activities, with IC50 values of 11.5, 18.5, and 18.1 μM, respectively. Furthermore, the hit compounds were chosen as probe molecules, and their probable interactions with the corresponding individual residues have been examined by jointly using the molecular docking, site-directed mutagenesis, enzymatic assays, and fluorescence spectra, to provide an insight into a new special binding-model located between the HMG-CoA and NADPH pockets. The good agreement between theoretical and experimental results indicate that the modeling strategies and screening processes in the present study are very likely to be a promising way to search novel lead compounds with both structural diversity and high inhibitory activity against SP-HMGR-II in the future.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Li D,Gui J,Li Y,Feng L,Han X,Sun Y,Sun T,Chen Z,Cao Y,Zhang Y,Zhou L,Hu X,Ren Y,Wan Jdoi
10.1021/ci300163vsubject
Has Abstractpub_date
2012-07-23 00:00:00pages
1833-41issue
7eissn
1549-9596issn
1549-960Xjournal_volume
52pub_type
杂志文章abstract：:We investigate unexpectedly short non-covalent distances (<85% of the sum of van der Waals radii) in X-ray crystal structures of proteins. We curate over 11 000 high-quality protein crystal structures and an ultra-high-resolution (1.2 Å or better) subset containing >900 structures. Although our non-covalent distance c...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00144
更新日期：2019-05-28 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：:Protein-protein interactions (PPIs) play vital roles in regulating biological processes, such as cellular and signaling pathways. Hotspots are certain residues located at protein-protein interfaces that contribute more in protein-protein binding than other residues. Research on the mutational effects of hotspots is im...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00966
更新日期：2021-01-25 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：:Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00660
更新日期：2016-04-25 00:00:00
abstract：:One tactic for cysteine protease inhibition is to form a covalent bond between an electrophilic atom of the inhibitor and the thiol of the catalytic cysteine. In this study, we evaluate the reaction free energy obtained from a hybrid quantum mechanical/molecular mechanical (QM/MM) free energy profile as a predictor of...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00847
更新日期：2020-02-24 00:00:00
abstract：:The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open co...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00721
更新日期：2018-07-23 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：: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：: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：:Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal, and metabolic abnormalities, while avoiding the psychoactive effects in the central nervous system. We applied our in-house algorithm, iterative stochastic elimination, to produc...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.9b00577
更新日期：2019-09-23 00:00:00
abstract：:Whereas 400 million distinct compounds are now purchasable within the span of a few weeks, the biological activities of most are unknown. To facilitate access to new chemistry for biology, we have combined the Similarity Ensemble Approach (SEA) with the maximum Tanimoto similarity to the nearest bioactive to predict a...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00316
更新日期：2018-01-22 00:00:00
abstract：:Understanding the relationship between chemical structure and function is a ubiquitous problem within the fields of chemistry and biology. Simulation approaches attack the problem utilizing physics to understand a given process at the particle level. Unfortunately, these approaches are often too expensive for many pro...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci8001233
更新日期：2008-08-01 00:00:00
abstract：:Protein dynamics play a critical role in ligand binding, and different models have been proposed to explain the relationships between protein motion and molecular recognition. Here, we present a study of ligand-binding processes associated with large conformational changes of a protein to elucidate the critical choice...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00125
更新日期：2017-07-24 00:00:00
abstract：:In this work, the perception of similarity of reactions catalyzed by hydrolases and oxidoreductases on the basis of the overall breaking and making of bonds of reactions is investigated. Six physicochemical properties for the reacting bond in the substrate of each enzymatic reaction were calculated to describe the cha...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci9004833
更新日期：2010-06-28 00:00:00
abstract：:The chronic toxicity is fundamental for toxicological risk assessment, but its correlation with the chemical structures has been studied only little. This is partly due to the complexity of such an experimental test that embraces a plethora of different biological effects and mechanisms of action, making (Q)SAR studie...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci8001974
更新日期：2008-10-01 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
abstract：:A database of about 700 high-resolution kinase structures was used to test the reliability of 17 docking procedures (using six docking software packages) by means of self- and cross-docking studies. The analysis of about 80 000 docking calculations suggests that the docking of an unknown ligand into a kinase has a pro...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci100161z
更新日期：2010-08-23 00:00:00
abstract：:3-Pyridyl ethers are excellent nAChRs ligands, which show high subtype selectivity and binding affinity to alpha4beta2 nAChR. Although the quantitative structure-activity relationship (QSAR) of nAChRs ligands has been widely investigated using various classes of compounds, the open ring analogues of 3-pyridyl ethers h...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0498113
更新日期：2005-03-01 00:00:00
abstract：:Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphoshatase (cy-FBP/SBPase) is a potential enzymatic target for screening of novel inhibitors that can combat harmful algal blooms. In the present study, we targeted the substrate binding pocket of cy-FBP/SBPase. A series of novel hit compounds from the SPECs database w...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci4007529
更新日期：2014-03-24 00:00:00
abstract：:The balance between structural stability and functional plasticity in proteins that share common three-dimensional folds is the key factor that drives protein evolvability. The ability to distinguish the parts of homologous proteins that underlie common structural organization patterns from the parts acting as regulat...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.6b00504
更新日期：2017-04-24 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：:Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta activation may el...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci900316e
更新日期：2009-11-01 00:00:00
abstract：:Inhibition of plasmin has been found to effectively reduce fibrinolysis and to avoid hemorrhage. This can be achieved by addressing its kringle 1 domain with the known drug and lysine analogue tranexamic acid. Guided by shape similarities toward a previously discovered lead compound, 5-(4-piperidyl)isoxazol-3-ol, a se...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.7b00255
更新日期：2017-07-24 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：:Representative molecules from 10 classes of prohibited substances were taken from the World Anti-Doping Agency (WADA) list, augmented by molecules from corresponding activity classes found in the MDDR database. Together with some explicitly allowed compounds, these formed a set of 5245 molecules. Five types of fingerp...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci0601160
更新日期：2006-11-01 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：:Great attention has been paid to the clinical significance of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil widely used for erectile dysfunction. However, sildenafil causes side effects on visual functions since it shows similar potencies to inhibit PDE5 and PDE6, whereas tadalaf...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400458z
更新日期：2013-11-25 00:00:00
abstract：:Characterizing the variability within an ensemble of protein structures is a common requirement in structural biology and bioinformatics. With the increasing number of protein structures becoming available, there is a need for new tools capable of automating the structural comparison of large ensemble of structures. W...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400233j
更新日期：2013-09-23 00:00:00
abstract：:Increasing protein kinase C (PKC) activity is of potential therapeutic value. Its activation involves an interaction between the C1 domain and diacylglycerol (DAG) at intracellular membrane surfaces; DAG mimetics hold promise as new drugs. We previously developed the isophthalate derivative HMI-1a3, an effective but h...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.0c00624
更新日期：2020-11-23 00:00:00
