Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach.


:Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects individuals worldwide, and is a leading cause of severe congenital neurologic and ocular disease in humans. No vaccine to protect humans is available, and hypersensitivity and toxicity limit the use of the few available medicines. Therefore, safer and more effective medicines to treat toxoplasmosis are urgently needed. Using the Hybrid Structure Based (HSB) method, we have previously identified small molecule inhibitors of P. falciparum that seem to target a novel protein-protein interaction between the Myosin tail interacting protein and myosin light chain. This pathway has been hypothesized to be involved in invasion of host erythrocytes by the parasite and is broadly conserved among the apicomplexans. Guided by similar computational drug design approaches, we investigated this series of small molecules as potential inhibitors of T. gondii. Compound C3-21, identified as the most active inhibitor in this series, exhibited an IC(50) value ~500 nM against T. gondii. Among the 16 structural analogs of C3-21 tested thus far, nine additional compounds were identified with IC(50) values <10.0 μM. In vitro assays have revealed that C3-21 markedly limits intracellular growth of T. gondii tachyzoites, but has no effect on host cell human foreskin fibroblasts (HFF) at concentrations more than a log greater than the concentration that inhibits the parasites.


J Comput Aided Mol Des


Kortagere S,Mui E,McLeod R,Welsh WJ




Has Abstract


2011-05-01 00:00:00












  • Count on kappa.

    abstract::In the 1960s, the kappa statistic was introduced for the estimation of chance agreement in inter- and intra-rater reliability studies. The kappa statistic was strongly pushed by the medical field where it could be successfully applied via analyzing diagnoses of identical patient groups. Kappa is well suited for classi...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Czodrowski P

    更新日期:2014-11-01 00:00:00

  • Comparison of conformer distributions in the crystalline state with conformational energies calculated by ab initio techniques.

    abstract::The conformational preferences of 12 molecular substructures in the crystalline state have been determined and compared with those predicted for relevant model compounds by ab initio molecular orbital calculations. Least-squares regression shows that there is a statistically significant correlation between the crystal...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Allen FH,Harris SE,Taylor R

    更新日期:1996-06-01 00:00:00

  • Modelling of carbohydrate-aromatic interactions: ab initio energetics and force field performance.

    abstract::Aromatic amino acid residues are often present in carbohydrate-binding sites of proteins. These binding sites are characterized by a placement of a carbohydrate moiety in a stacking orientation to an aromatic ring. This arrangement is an example of CH/pi interactions. Ab initio interaction energies for 20 carbohydrate...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Spiwok V,Lipovová P,Skálová T,Vondrácková E,Dohnálek J,Hasek J,Králová B

    更新日期:2005-12-01 00:00:00

  • Charge density distributions derived from smoothed electrostatic potential functions: design of protein reduced point charge models.

    abstract::To generate reduced point charge models of proteins, we developed an original approach to hierarchically locate extrema in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions. A charge fitting program was used to assign charge valu...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Leherte L,Vercauteren DP

    更新日期:2011-10-01 00:00:00

  • Classification of protein disulphide-bridge topologies.

    abstract::The preferential occurrence of certain disulphide-bridge topologies in proteins has prompted us to design a method and a program, KNOT-MATCH, for their classification. The program has been applied to a database of proteins with less than 65% homology and more than two disulphide bridges. We have investigated whether t...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Mas JM,Aloy P,Martí-Renom MA,Oliva B,de Llorens R,Avilés FX,Querol E

    更新日期:2001-05-01 00:00:00

  • Efficient overlay of small organic molecules using 3D pharmacophores.

    abstract::Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity meas...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Wolber G,Dornhofer AA,Langer T

    更新日期:2006-12-01 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


    authors: Brylinski M,Feinstein WP

    更新日期:2013-06-01 00:00:00

  • Atomistic computer simulations on multi-loaded PAMAM dendrimers: a comparison of amine- and hydroxyl-terminated dendrimers.

    abstract::Poly(amidoamine) (PAMAM) dendrimers have been extensively studied as delivery vectors in biomedical applications. A limited number of molecular dynamics (MD) simulation studies have investigated the effect of surface chemistry on therapeutic molecules loading, with the aim of providing insights for biocompatibility im...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Badalkhani-Khamseh F,Ebrahim-Habibi A,Hadipour NL

    更新日期:2017-12-01 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


    authors: Mills JE,Perkins TD,Dean PM

    更新日期:1997-05-01 00:00:00

  • Side chain virtual screening of matched molecular pairs: a PDB-wide and ChEMBL-wide analysis.

    abstract::Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Baumgartner MP,Evans DA

    更新日期:2020-09-01 00:00:00

  • Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition.

    abstract::A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogen...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Celis-Barros C,Saavedra-Rivas L,Salgado JC,Cassels BK,Zapata-Torres G

    更新日期:2015-01-01 00:00:00

  • Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK.

    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


    authors: Vinh NB,Simpson JS,Scammells PJ,Chalmers DK

    更新日期:2012-04-01 00:00:00

  • Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes.

    abstract::A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-based method were applied on a database holding the 3D structures of 29 thrombin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimentally determined bind...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Bursi R,Grootenhuis PD

    更新日期:1999-05-01 00:00:00

  • Combining NMR spectral and structural data to form models of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls binding to the AhR.

    abstract::A three-dimensional quantitative spectrometric data-activity relationship (3D-QSDAR) modeling technique which uses NMR spectral and structural information that is combined in a 3D-connectivity matrix has been developed. A 3D-connectivity matrix was built by displaying all possible assigned carbon NMR chemical shifts, ...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Beger RD,Buzatu DA,Wilkes JG

    更新日期:2002-10-01 00:00:00

  • Strategic approaches to drug design. II. Modelling studies on phosphodiesterase substrates and inhibitors.

    abstract::Modelling studies have been carried out on the phosphodiesterase (PDE) substrates, adenosine- and guanosine-3'5'-cyclic monophosphates, and on a number of non-specific and type III-specific phosphodiesterase inhibitors. These studies have assisted the understanding of PDE substrate differentiation and the design of po...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Davis A,Warrington BH,Vinter JG

    更新日期:1987-07-01 00:00:00

  • AstexViewer: a visualisation aid for structure-based drug design.

    abstract::AstexViewer is a Java molecular graphics program that can be used for visualisation in many aspects of structure-based drug design. This paper describes its functionality, implementation and examples of its use. The program can run as an Applet in a web browser allowing structures to be displayed without installing ad...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Hartshorn MJ

    更新日期:2002-12-01 00:00:00

  • Computer simulation of the binding of amonafide and azonafide to DNA.

    abstract::Intercalative binding of the antitumor drugs amonafide and azonafide to the oligonucleotide duplex d(GGCCGGCCGG).d(CCGGCCGGCC) was compared using molecular dynamics in vacuum with the AMBER force field. A number of reasonable possible binding conformations were obtained, with the azonafide complexes favored over the a...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Bear S,Remers WA

    更新日期:1996-04-01 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


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

    更新日期:1998-11-01 00:00:00

  • QSAR without arbitrary descriptors: the electron-conformational method.

    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


    authors: Bersuker IB

    更新日期:2008-06-01 00:00:00

  • CoMFA validation of the superposition of six classes of compounds which block GABA receptors non-competitively.

    abstract::Thirty-six compounds, representing six different structural classes of insecticides which are known to act at the gamma-aminobutyric acid receptor/chloride ionophore, have been superimposed by methods which maximise the commonality of steric and electrostatic fields. Maximal steric and electrostatic alignment was deri...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Calder JA,Wyatt JA,Frenkel DA,Casida JE

    更新日期:1993-02-01 00:00:00

  • Substrate recognition by norovirus polymerase: microsecond molecular dynamics study.

    abstract::Molecular dynamics simulations of complexes between Norwalk virus RNA dependent RNA polymerase and its natural CTP and 2dCTP (both containing the O5'-C5'-C4'-O4' sequence of atoms bridging the triphosphate and sugar moiety) or modified coCTP (C5'-O5'-C4'-O4'), cocCTP (C5'-O5'-C4'-C4'') substrates were produced by mean...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Maláč K,Barvík I

    更新日期:2013-04-01 00:00:00

  • Genetic algorithm for the design of molecules with desired properties.

    abstract::The design of molecules with desired properties is still a challenge because of the largely unpredictable end results. Computational methods can be used to assist and speed up this process. In particular, genetic algorithms have proved to be powerful tools with a wide range of applications, e.g. in the field of drug d...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Kamphausen S,Höltge N,Wirsching F,Morys-Wortmann C,Riester D,Goetz R,Thürk M,Schwienhorst A

    更新日期:2002-08-01 00:00:00

  • Computational studies of new potential antimalarial compounds--stereoelectronic complementarity with the receptor.

    abstract::One of the most important pharmacological mechanisms of antimalarial action is the inhibition of the aggregation of hematin into hemozoin. We present a group of new potential antimalarial molecules for which we have performed a DFT study of their stereoelectronic properties. Additionally, the same calculations were ca...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Portela C,Afonso CM,Pinto MM,Ramos MJ

    更新日期:2003-09-01 00:00:00

  • Blind prediction of cyclohexane-water distribution coefficients from the SAMPL5 challenge.

    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


    authors: Bannan CC,Burley KH,Chiu M,Shirts MR,Gilson MK,Mobley DL

    更新日期:2016-11-01 00:00:00

  • 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 int...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Böhm HJ

    更新日期:1992-02-01 00:00:00

  • Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations.

    abstract::We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource ( https://drugdesigndata.org/ ). The challenge was focused on the ligands of the farnesoid X rece...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Yakovenko O,Jones SJM

    更新日期:2018-01-01 00:00:00

  • New designs for MRI contrast agents.

    abstract::New designs for Magnetic Resonance Imaging contrast agents are presented. Essentially, they all are host-guest inclusion complexes between y-cyclodextrins and polyazamacrocycles of gadolinium (III) ion. Substitutions have been made to the host to optimise the host-guest association. Molecular mechanics calculations ha...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Fernandes PA,Carvalho AT,Marques AT,Pereira AL,Madeira AP,Ribeiro AS,Carvalho AF,Ricardo ET,Pinto FJ,Santos HA,Mangericão HD,Martins HM,Pinto HD,Santos HR,Moreira IS,Azeredo MJ,Abreu RP,Oliveira RM,Sousa SF,Silva RJ

    更新日期:2003-07-01 00:00:00

  • Making priors a priority.

    abstract::When we build a predictive model of a drug property we rigorously assess its predictive accuracy, but we are rarely able to address the most important question, "How useful will the model be in making a decision in a practical context?" To answer this requires an understanding of the prior probability distribution ("t...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Segall M,Chadwick A

    更新日期:2010-12-01 00:00:00

  • Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2.

    abstract::Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to app...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Rifai EA,van Dijk M,Vermeulen NPE,Geerke DP

    更新日期:2018-01-01 00:00:00

  • Property distribution of drug-related chemical databases.

    abstract::The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters,...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章


    authors: Oprea TI

    更新日期:2000-03-01 00:00:00