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 interaction sites, which are discrete positions in space suitable to form hydrogen bonds or to fill a hydrophobic pocket. The interaction sites are derived from distributions of nonbonded contacts generated by a search through the Cambridge Structural Database. An alternative route to generate the interaction sites is the use of rules. The second step is the fit of molecular fragments onto the interaction sites. Currently we use a library of 600 fragments for the fitting. The final step in the present program is the connection of some or all of the fitted fragments to a single molecule. This is done by bridge fragments. Applications are presented for the crystal packing of benzoic acid and the enzymes dihydrofolate reductase and trypsin.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Böhm HJdoi
10.1007/BF00124387subject
Has Abstractpub_date
1992-02-01 00:00:00pages
61-78issue
1eissn
0920-654Xissn
1573-4951journal_volume
6pub_type
杂志文章abstract::A dataset of 82 protein-ligand complexes of known 3D structure and binding constant Ki was analysed to elucidate the important factors that determine the strength of protein-ligand interactions. The following parameters were investigated: the number and geometry of hydrogen bonds and ionic interactions between the pro...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章,评审
doi:10.1023/a:1007999920146
更新日期:1998-07-01 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::The binding mode of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-ami dino-2- naphthyl)propanoic acid hydrochloride (DX-9065a, 4) to Factor Xa is examined using inhibition data for a series of analogs that have a hydrophobic group as well as basic or dibasic functionality. Comparative molecular field ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007969517376
更新日期:1998-03-01 00:00:00
abstract::The pKa is the standard measure used to describe the aqueous proton affinity of a compound, indicating the proton concentration (pH) at which two protonation states (e.g. A- and AH) have equal free energy. However, compounds can have additional protonation states (e.g. AH2+), and may assume multiple tautomeric forms, ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00280-7
更新日期:2020-05-01 00:00:00
abstract::Two different types of approaches: (a) approaches that combine quantitative structure activity relationships, quantum mechanical electronic structure methods, and machine-learning and, (b) electronic structure vertical solvation approaches, were used to predict the logP coefficients of 11 molecules as part of the SAMP...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00287-0
更新日期:2020-05-01 00:00:00
abstract::Drug discovery is an expensive and time-consuming process. To make this process more efficient quantum chemistry methods can be employed. The electrophilicity index is one property that can be calculated by quantum chemistry methods, and if calculated correctly gives insight into the reactivity of covalent inhibitors....
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00342-w
更新日期:2020-10-05 00:00:00
abstract::A linear quantitative-structure activity relationship model is developed in this work using Multiple Linear Regression Analysis as applied to a series of 51 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides derivatives with CCR5 binding affinity. For the selection of the best variables the Elimination Selection-Step...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9038-2
更新日期:2006-02-01 00:00:00
abstract::Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-012-9620-8
更新日期:2012-12-01 00:00:00
abstract::Orientation of ten water molecules bound strongly at the contact surface of the dihydrofolate reductase-methotrexate enzyme-inhibitor complex was determined theoretically. To optimize the orientation of the water molecules, a recent method based on a simple electrostatic model was applied. The electrostatic complement...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01532054
更新日期:1988-04-01 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::Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different cl...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9757-8
更新日期:2014-07-01 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::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::Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00126666
更新日期:1991-08-01 00:00:00
abstract::We have derived a model of the nicotinic acetylcholine binding site. This was accomplished by using three known agonists (acetylcholine, nicotine and epibatidine) as templates around which polypeptide side chains, found to be part of the receptor cavity from published molecular biology studies, are allowed to flow fre...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008029924865
更新日期:1999-01-01 00:00:00
abstract::An evolutionary algorithm was developed for fragment-based de novo design of molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of approximately 25,000 fragment structures serves as the building block supply, which w...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008184403558
更新日期:2000-07-01 00:00:00
abstract::The previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124342
更新日期:1991-06-01 00:00:00
abstract::Molecular structures and functions of the majority of proteins across different species are yet to be identified. Much needed functional annotation of these gene products often benefits from the knowledge of protein-ligand interactions. Towards this goal, we developed eFindSite, an improved version of FINDSITE, design...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-013-9663-5
更新日期:2013-06-01 00:00:00
abstract::A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson-Boltzmann and surface area calculations) to estimate protein-ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 A from the ligand. This system is freely...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9238-z
更新日期:2009-02-01 00:00:00
abstract::Moment descriptors of the molecular charge and mass distributions are investigated within the context of molecular similarity. Euclidean distances in the moment descriptor space are shown to yield molecular proximities in accord with chemical intuition for a substituted [(4-phenylpiperazinyl)-methyl] benzamide series ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008064003409
更新日期:1998-11-01 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::Starting from the X-ray structure of a class I major histocompatibility complex (MHC)-encoded protein (HLA-B*2705), a naturally presented self-nonapeptide and two synthetic analogues were simulated in the binding groove of two human leukocyte antigen (HLA) alleles (B*2703 and B*2705) differing in a single amino acid r...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007963901092
更新日期:1997-09-01 00:00:00
abstract::We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand a...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-018-0126-x
更新日期:2018-07-01 00:00:00
abstract::The Epstein-Barr Nuclear Antigen 1 (EBNA1) is a critical protein encoded by the Epstein-Barr Virus (EBV). During latent infection, EBNA1 is essential for DNA replication and transcription initiation of viral and cellular genes and is necessary to immortalize primary B-lymphocytes. Nonetheless, the concept of EBNA1 as ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9899-y
更新日期:2016-04-01 00:00:00
abstract::Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad ran...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-004-7878-1
更新日期:2004-12-01 00:00:00
abstract::Hydrogen bonds are the most specific, and therefore predictable of the intermolecular interactions involved in ligand-protein binding. Given the structure of a molecule, it is possible to estimate the positions at which complementary hydrogen-bonding atoms could be found. Crystal-survey data are used in the design of ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007900527102
更新日期:1997-05-01 00:00:00
abstract::The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule i...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-019-00211-1
更新日期:2019-07-01 00:00:00
abstract::A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to th...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00134180
更新日期:1996-12-01 00:00:00
abstract::Recent progress in molecular biology has revealed that many non-coding RNAs regulate gene expression or catalyze biochemical reactions in tumors, viruses and several other diseases. The tertiary structure of RNA molecules and RNA-RNA/protein interaction sites are of increasing importance as potential targets for new m...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-019-00195-y
更新日期:2019-05-01 00:00:00
abstract::The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed th...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-0005-2
更新日期:2017-02-01 00:00:00