Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase

Frecer, Vladimı́r; Megnassan, Eugène; Miertus, Stanislav

doi:10.1016/j.ejmech.2008.12.028

Cited by 31 publications

(35 citation statements)

References 33 publications

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“…1 and observed activities pK i pre /pK i exp , which yielded values close to 1, confirmed the predictive power of the QSAR model. Although the training and validation sets displayed somewhat limited variation in the R-groups space due to restricted availability of experimental data, prediction of inhibitory potencies by the trained targetspecific scoring function, which slightly exceed the activity ranges of the training set, is still possible, as QSAR models using ligand-receptor binding affinity estimate (LUDI score) of docked analogs are less sensitive to size of the training set [33][34][35][36].…”

Section: Qsar Model and Target-specific Scoring Functionmentioning

confidence: 99%

“…1). A virtual library of more than 9,200 analogs containing natural and especially unusual amino acids was designed, structure-based focused and in silico screened by computer-assisted combinatorial techniques [33][34][35][36] aiming at finding more potent and specific antiviral compounds. The three-dimensional structure of the DEN2 NS2B-NS3pro complex was employed to develop a QSAR model, parameterize a target-specific scoring function specific for the NS3pro target and select analogues which display the highest predicted binding to the NS3pro.…”

Section: Admementioning

confidence: 99%

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Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

Frecer

Miertus²

2010

J Comput Aided Mol Des

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Serine protease activity of the NS3 protein of Dengue virus is an important target of antiviral agents that interfere with the viral polyprotein precursor processing catalyzed by the NS3 protease (NS3pro), which is important for the viral replication and maturation. Recent studies showed that substrate-based peptidomimetics carrying an electrophilic warhead inhibit the NS2B-NS3pro cofactor-protease complex with inhibition constants in the low micromolar concentration range when basic amino acid residues occupy P(1) and P(2) positions of the inhibitor, and an aldehyde warhead is attached to the P(1). We have used computer-assisted combinatorial techniques to design, focus using the NS2B-NS3pro receptor 3D structure, and in silico screen a virtual library of more than 9,200 peptidomimetic analogs targeted around the template inhibitor Bz-Nle-Lys-Arg-Arg-H (Bz-benzoyl) that are composed mainly of unusual amino acid residues in all positions P(1)-P(4). The most promising virtual hits were analyzed in terms of computed enzyme-inhibitor interactions and Adsorption, Distribution, Metabolism and Excretion (ADME) related physico-chemical properties. Our study can direct the interest of medicinal chemists working on a next generation of antiviral chemotherapeutics against the Dengue Fever towards the explored subset of the chemical space that is predicted to contain peptide aldehydes with NS3pro inhibition potencies in nanomolar range which display ADME-related properties comparable to the training set inhibitors.

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Section: Qsar Model and Target-specific Scoring Functionmentioning

confidence: 99%

Section: Admementioning

confidence: 99%

Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

Frecer

Miertus²

2010

J Comput Aided Mol Des

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“…In this work, we have virtually explored in an extensive manner the chemical space around VAN1 by designing and in silico screening a virtual library of 2 0 ,3 0 -bicyclic thymidine analogues using computer-assisted combinatorial techniques [24][25][26][27][28]. Our goal was to select more potent TMPK mt inhibitors endowed with favorable ADME-related properties, and to prioritize them for future synthesis.…”

Section: Introductionmentioning

confidence: 99%

Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Frecer

Seneci

Miertus

2010

J Comput Aided Mol Des

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Thymidine monophosphate kinase (TMPK(mt)) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2',3'-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2',3'-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK(mt) binding site. The three-dimensional structure of the TMPK(mt) complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK(mt) target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties.

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“…The virtual combinatorial chemistry technique, originating from efforts to efficiently synthesize libraries of diverse compounds, helps to shed light on the issue and thus provides a powerful approach to generate an in silico molecular structure library of SCCPs (Cho et al, 1998;Zhou, 2008). In fact, this method has developed rapidly and could generate thousands or even millions of chemical structures within a short time through correctly defined chemical reactions based on combinatorial theory and computational simulation (Frecer et al, 2009;Lokwani et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Chlorination pattern effect on thermodynamic parameters and environmental degradability for C 10 -SCCPs: Quantum chemical calculation based on virtual combinational library

Sun

Pan

Lin

et al. 2016

Journal of Environmental Sciences

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Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase

Cited by 31 publications

References 33 publications

Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Chlorination pattern effect on thermodynamic parameters and environmental degradability for C 10 -SCCPs: Quantum chemical calculation based on virtual combinational library

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