The computer program LUDI: a new method for the de novo design of enzyme inhibitors.

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 Des

authors

Böhm HJ

doi

10.1007/BF00124387

subject

Has Abstract

pub_date

1992-02-01 00:00:00

pages

61-78

issue

1

eissn

0920-654X

issn

1573-4951

journal_volume

6

pub_type

杂志文章
  • Prediction of binding constants of protein ligands: a fast method for the prioritization of hits obtained from de novo design or 3D database search programs.

    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

    authors: Böhm HJ

    更新日期:1998-07-01 00:00:00

  • Pharmacophore model for bile acids recognition by the FPR receptor.

    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

    authors: Ferrari C,Macchiarulo A,Costantino G,Pellicciari R

    更新日期:2006-05-01 00:00:00

  • Evaluation of proposed modes of binding of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-am idino- 2- naphthyl)propanoic acid hydrochloride and some analogs to factor Xa using a comparative molecular field analysis.

    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

    authors: Vaz RJ,McLean LR,Pelton JT

    更新日期:1998-03-01 00:00:00

  • Standard state free energies, not pKas, are ideal for describing small molecule protonation and tautomeric states.

    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

    authors: Gunner MR,Murakami T,Rustenburg AS,Işık M,Chodera JD

    更新日期:2020-05-01 00:00:00

  • SAMPL6 logP challenge: machine learning and quantum mechanical approaches.

    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

    authors: Patel P,Kuntz DM,Jones MR,Brooks BR,Wilson AK

    更新日期:2020-05-01 00:00:00

  • Covalent inhibitor reactivity prediction by the electrophilicity index-in and out of scope.

    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

    authors: Hermann MR,Pautsch A,Grundl MA,Weber A,Tautermann CS

    更新日期:2020-10-05 00:00:00

  • Investigation of substituent effect of 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides on CCR5 binding affinity using QSAR and virtual screening techniques.

    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

    authors: Afantitis A,Melagraki G,Sarimveis H,Koutentis PA,Markopoulos J,Igglessi-Markopoulou O

    更新日期:2006-02-01 00:00:00

  • Free enthalpies of replacing water molecules in protein binding pockets.

    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

    authors: Riniker S,Barandun LJ,Diederich F,Krämer O,Steffen A,van Gunsteren WF

    更新日期:2012-12-01 00:00:00

  • Orientation and structure-building role of the water molecules bound at the contact surface of the dihydrofolate reductase-methotrexate complex.

    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

    authors: Nagy P

    更新日期:1988-04-01 00:00:00

  • Comparison of commercially available genetic algorithms: gas as variable selection tool.

    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

    authors: Schefzick S,Bradley M

    更新日期:2004-07-01 00:00:00

  • Ligand efficiency metrics considered harmful.

    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

    authors: Kenny PW,Leitão A,Montanari CA

    更新日期:2014-07-01 00:00:00

  • D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors.

    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

    authors: Sasmal S,El Khoury L,Mobley DL

    更新日期:2020-02-01 00:00:00

  • All-atom/coarse-grained hybrid predictions of distribution coefficients in SAMPL5.

    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

    authors: Genheden S,Essex JW

    更新日期:2016-11-01 00:00:00

  • The discovery of novel auxin transport inhibitors by molecular modeling and three-dimensional pattern analysis.

    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

    authors: Bures MG,Black-Schaefer C,Gardner G

    更新日期:1991-08-01 00:00:00

  • A computational model of the nicotinic acetylcholine binding site.

    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

    authors: Gálvez-Ruano E,Iriepa-Canalda I,Morreale A,Lipkowitz KB

    更新日期:1999-01-01 00:00:00

  • De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks.

    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

    authors: Schneider G,Lee ML,Stahl M,Schneider P

    更新日期:2000-07-01 00:00:00

  • The computational design of test compounds with potentially specific biological activity: histamine-H2 agonists derived from 5-HT/H2 antagonists.

    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

    authors: Topiol S,Sabio M

    更新日期:1991-06-01 00:00:00

  • eFindSite: improved prediction of ligand binding sites in protein models using meta-threading, machine learning and auxiliary ligands.

    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

    authors: Brylinski M,Feinstein WP

    更新日期:2013-06-01 00:00:00

  • An improved method to predict the entropy term with the MM/PBSA approach.

    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

    authors: Kongsted J,Ryde U

    更新日期:2009-02-01 00:00:00

  • Molecular moment similarity between clozapine and substituted [(4-phenylpiperazinyl)-methyl] benzamides: selective dopamine D4 agonists.

    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

    authors: Silverman BD,Pitman MC,Platt DE,Rigoutsos I

    更新日期:1998-11-01 00:00:00

  • QXP: powerful, rapid computer algorithms for structure-based drug design.

    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

    authors: McMartin C,Bohacek RS

    更新日期:1997-07-01 00:00:00

  • Fine specificity of antigen binding to two class I major histocompatibility proteins (B*2705 and B*2703) differing in a single amino acid residue.

    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

    authors: Rognan D,Krebs S,Kuonen O,Lamas JR,López de Castro JA,Folkers G

    更新日期:1997-09-01 00:00:00

  • Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose.

    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

    authors: Cleves AE,Jain AN

    更新日期:2018-07-01 00:00:00

  • Computational analysis of EBNA1 "druggability" suggests novel insights for Epstein-Barr virus inhibitor design.

    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

    authors: Gianti E,Messick TE,Lieberman PM,Zauhar RJ

    更新日期:2016-04-01 00:00:00

  • Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model.

    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

    authors: Kettmann V,Kost'álová D,Höltje HD

    更新日期:2004-12-01 00:00:00

  • An automated method for predicting the positions of hydrogen-bonding atoms in binding sites.

    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

    authors: Mills JE,Perkins TD,Dean PM

    更新日期:1997-05-01 00:00:00

  • Rational creation and systematic analysis of cervical cancer kinase-inhibitor binding profile.

    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

    authors: Han M,Sun D

    更新日期:2019-07-01 00:00:00

  • A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists.

    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

    authors: Belvisi L,Bravi G,Catalano G,Mabilia M,Salimbeni A,Scolastico C

    更新日期:1996-12-01 00:00:00

  • ToGo-WF: prediction of RNA tertiary structures and RNA-RNA/protein interactions using the KNIME workflow.

    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

    authors: Yamasaki S,Amemiya T,Yabuki Y,Horimoto K,Fukui K

    更新日期:2019-05-01 00:00:00

  • Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations.

    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

    authors: Liu K,Watanabe E,Kokubo H

    更新日期:2017-02-01 00:00:00