Abstract：
:We employed a combination of molecular docking and dynamics to understand the interaction of three different radical scavengers (SB-HSC21, ABNM13 and trimidox) with ribonucleotide reductase M2 (hRRM2) domain. On the basis of the observed results, we can propose how these ligands interact with the enzyme, and cease the radical transfer step from the di-iron center to TYR176. All the ligands alter the electron density over TYR176, -OH group by forming an extremely stable H-bond with either -NHOH group, or with phenolic hydroxyl group of the ligands. This change in electronic density disrupts the water bridge between TYR176, -OH and the di-iron center, which stops the single electron transfer process from TYR176, -OH to iron. As a consequence the enzyme is inhibited. Another interesting observation that we are reporting is the two stage gate keeping mechanism of the RR active site tunnel. We describe these as the outer Gate-1 controlled by ARG330, and the inner Gate-2 controlled by SER263, PHE240, and PHE236. We also observed a dynamic conformational shift in these residues, the incoming ligands can go through, and interact with the underlying TYR176, -OH group. From the study we found the active-site of hRRM2 is extremely flexible and shows a significant induced fit.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Basu A,Sinha BNdoi
10.1007/s10822-012-9581-ysubject
Has Abstractpub_date
2012-07-01 00:00:00pages
865-81issue
7eissn
0920-654Xissn
1573-4951journal_volume
26pub_type
杂志文章abstract：:We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (str...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9569-7
更新日期：2012-04-01 00:00:00
abstract：:We present blind predictions submitted to the SAMPL5 challenge on calculating distribution coefficients. The predictions were based on estimating the solvation free energies in water and cyclohexane of the 53 compounds in the challenge. These free energies were computed using alchemical free energy simulations based o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9926-z
更新日期：2016-11-01 00:00:00
abstract：:Patents from medicinal chemistry represent a rich source of novel compounds and activity data that appear only infrequently in the scientific literature. Moreover, patent information provides a primary focal point for drug discovery. Accordingly, text mining and image extraction approaches have become hot topics in pa...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0061-2
更新日期：2017-09-01 00:00:00
abstract：:Formyl-peptide receptors (FPRs) belong to the family A of the G-protein coupled receptor superfamily and include three subtypes: FPR, FPR-like-1 and FPR-like-2. They have been involved in the control of many inflammatory processes promoting the recruitment and infiltration of leukocytes in regions of inflammation thro...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-006-9055-1
更新日期：2006-05-01 00:00:00
abstract：:Both society and industry are interested in increasing the safety of pharmaceuticals. Potentially dangerous compounds could be filtered out at early stages of R&D by computer prediction of biological activity and ADMET characteristics. Accuracy of such predictions strongly depends on the quality & quantity of informat...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-005-9014-2
更新日期：2005-09-01 00:00:00
abstract：:The electron-conformational (EC) method in QSAR problems employs a unique (based on first principles) descriptor of molecular properties that incorporates the electronic structure and topology of the molecule and is presented in a digital-matrix form suitable for computer processing, the EC matrix of congruity (ECMC)....
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-008-9191-x
更新日期：2008-06-01 00:00:00
abstract：:Accurate and well-curated experimental pKa data of organic acids and bases in both aqueous and non-aqueous media are invaluable in many areas of chemical research, including pharmaceutical, agrochemical, specialty chemical and property prediction research. In pharmaceutical research, pKa data are relevant in ligand de...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9764-9
更新日期：2014-10-01 00:00:00
abstract：:Many commercially available software programs claim similar efficiency and accuracy as variable selection tools. Genetic algorithms are commonly used variable selection methods where most relevant variables can be differentiated from 'less important' variables using evolutionary computing techniques. However, differen...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-004-5322-1
更新日期：2004-07-01 00:00:00
abstract：:The support vector machine, which is a novel algorithm from the machine learning community, was used to develop quantitation and classification models which can be used as a potential screening mechanism for a novel series of COX-2 selective inhibitors. Each compound was represented by calculated structural descriptor...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-004-2722-1
更新日期：2004-06-01 00:00:00
abstract：:We describe a software tool that allows one to visualize and analyze the importance of each individual steric interaction in a molecular mechanics force field. ANLIZE is presently implemented for the Dreiding force field for use with the Cerius2 software package, but could be implemented in any molecular mechanics pac...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008070106973
更新日期：1997-03-01 00:00:00
abstract：:Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression. Thus, they are of interest as a starting point for drug design. In this respect, potent non-hydrolysable derivatives such as thioglycosides are of specia...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9301-4
更新日期：2009-12-01 00:00:00
abstract：:A method has been developed that allows one to drive a molecule to conformations of lowest energy given the starting conformation, the identity of the rotatable bonds and the step size. This method has proved useful in our hands in the drug design arena where it is frequently more important to get 'low-energy' conform...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00117278
更新日期：1995-02-01 00:00:00
abstract：:We developed a new structure-based in-silico screening method using a negative image of a ligand-binding pocket and a multi-protein-compound interaction matrix. Based on the structure of the ligand pocket of the target protein, we designed a negative image, which consists of virtual atoms whose radii are close to thos...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-006-9047-1
更新日期：2006-04-01 00:00:00
abstract：:Several chiral vinylboranes have been theoretically evaluated as enantioselective Diels-Alder dienophiles. Theoretical results suggest that optically pure 2,5-diphenyl-1-vinyl-borolane should be the reagent of choice for performing such transformations efficiently. ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000035200.30340.41
更新日期：2004-03-01 00:00:00
abstract：:The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-0004-3
更新日期：2017-03-01 00:00:00
abstract：:An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydrophobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An exampl...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00135313
更新日期：1991-12-01 00:00:00
abstract：:In order to identify novel chemical classes of factor Xa inhibitors, five scoring functions (FlexX, DOCK, GOLD, ChemScore and PMF) were engaged to evaluate the multiple docking poses generated by FlexX. The compound collection was composed of confirmed potent factor Xa inhibitors and a subset of the LeadQuest screenin...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000047812.39758.ab
更新日期：2004-05-01 00:00:00
abstract：:In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screenin...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0093-7
更新日期：2018-02-01 00:00:00
abstract：:In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods w...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9954-8
更新日期：2016-11-01 00:00:00
abstract：:The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00249-1
更新日期：2020-02-01 00:00:00
abstract：:The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensio...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124460
更新日期：1996-02-01 00:00:00
abstract：:Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus li...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9263-6
更新日期：2009-06-01 00:00:00
abstract：:In previous studies we have developed categorical QSAR models for predicting skin-sensitization potency based on 4D-fingerprint (4D-FP) descriptors and in vivo murine local lymph node assay (LLNA) measures. Only 4D-FP derived from the ground state (GMAX) structures of the molecules were used to build the QSAR models. ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-008-9190-y
更新日期：2008-06-01 00:00:00
abstract：:In this work, the antimalarial activity of two series of 20 and 7 synthetic 1,2,4-trioxanes and a set of 20 cyclic peroxy ketals are tested for correlation search by means of Molecular Quantum Similarity Measures (MQSM). QSAR models, dealing with different biological responses (IC90, IC50 and ED90) of the parasite Pla...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1015917510236
更新日期：2001-12-01 00:00:00
abstract：:A new computer program is described, which positions small molecules into clefts of protein structures (e.g. an active site of an enzyme) in such a way that hydrogen bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic groups. The program works in three steps. First it calculates int...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124387
更新日期：1992-02-01 00:00:00
abstract：:The free fatty acid receptor 1 (FFAR1, formerly GPR40), is a potential G protein-coupled receptor (GPCR) target for the treatment of type 2 diabetes mellitus (T2DM), as it enhances glucose-dependent insulin secretion upon activation by endogenous long-chain free fatty acids. The presence of two allosterically communic...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-020-00338-6
更新日期：2020-11-01 00:00:00
abstract：:De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9473-6
更新日期：2011-10-01 00:00:00
abstract：:New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An ad...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007907728892
更新日期：1997-07-01 00:00:00
abstract：:The linear finite difference Poisson-Boltzmann (FDPB) equation is applied to the calculation of the electrostatic binding free energies of a group of inhibitors to the Neuraminidase enzyme. An ensemble of enzyme-inhibitor complex conformations was generated using Monte Carlo simulations and the electrostatic binding f...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008197913568
更新日期：2001-02-01 00:00:00
abstract：:Molecular modeling methodologies such as molecular docking, pharmacophore modeling, and 3D-QSAR, rely on conformational searches of small molecules as a starting point. All of these methodologies seek conformations of the small molecules as they bind to target proteins, i.e., their active conformations. Thus the quest...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1016320106741
更新日期：2002-02-01 00:00:00
