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901 KiB

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MMPBSA Decomposition of the Binding Energy throughout a Molecular Dynamics Simulation of Amyloid-Beta (Aß₁₀₋₃₅) Aggregation

by Josep M. Campanera and Ramon Pouplana

Molecules 2010, 15(4), 2730-2748; https://doi.org/10.3390/molecules15042730 - 15 Apr 2010

Cited by 35 | Viewed by 14709

Abstract

Recent experiments with amyloid-beta (Aβ) peptides indicate that the formation of toxic oligomers may be an important contribution to the onset of Alzheimer’s disease. The toxicity of Aβ oligomers depend on their structure, which is governed by assembly dynamics. However, a detailed knowledge of the structure of at the atomic level has not been achieved yet due to limitations of current experimental techniques. In this study, replica exchange molecular dynamics simulations are used to identify the expected diversity of dimer conformations of Aβ₁₀₋₃₅ monomers. The most representative dimer conformation has been used to track the dimer formation process between both monomers. The process has been characterized by means of the evolution of the decomposition of the binding free energy, which provides an energetic profile of the interaction. Dimers undergo a process of reorganization driven basically by inter-chain hydrophobic and hydrophilic interactions and also solvation/desolvation processes. Full article

(This article belongs to the Special Issue Combinatorial Chemistry)

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1264 KiB

Open AccessArticle

Preparation of 16β-Estradiol Derivative Libraries as Bisubstrate Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 Using the Multidetachable Sulfamate Linker

by Marie Bérubé, Florian Delagoutte and Donald Poirier

Molecules 2010, 15(3), 1590-1631; https://doi.org/10.3390/molecules15031590 - 10 Mar 2010

Cited by 9 | Viewed by 7932

Abstract

Combinatorial chemistry is a powerful tool used to rapidly generate a large number of potentially biologically active compounds. In our goal to develop bisubstrate inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) that interact with both the substrate (estrone or estradiol) and the cofactor (NAD(P)H) binding sites, we used parallel solid-phase synthesis to prepare three libraries of 16β-estradiol derivatives with two or three levels of molecular diversity. From estrone, we first synthesized a sulfamate precursor that we loaded on trityl chloride resin using the efficient multidetachable sulfamate linker strategy recently developed in our laboratory. We then introduced molecular diversity [one or two amino acid(s) followed by a carboxylic acid] on steroid nucleus by Fmoc peptide chemistry. Finally, after a nucleophilic cleavage, libraries of 30, 63 and 25 estradiol derivatives were provided. A library of 30 sulfamoylated estradiol derivatives was also generated by acidic cleavage and its members were screened for inhibition of steroid sulfatase. Biological evaluation on homogenated HEK-293 cells overexpressing 17β-HSD1 of the estradiol derivatives carrying different oligoamide-type chains at C-16 first revealed that three levels of molecular diversity (a spacer of two amino acids) were necessary to interact with the adenosine part of the cofactor binding site. Second, the best inhibition was obtained when hydrophobic residues (phenylalanine) were used as building blocks. Full article

(This article belongs to the Special Issue Combinatorial Chemistry)

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153 KiB

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Upgrading SELEX Technology by Using Lambda Exonuclease Digestion for Single-Stranded DNA Generation

by Meltem Avci-Adali, Angel Paul, Nadj Wilhelm, Gerhard Ziemer and Hans Peter Wendel

Molecules 2010, 15(1), 1-11; https://doi.org/10.3390/molecules15010001 - 24 Dec 2009

Cited by 115 | Viewed by 18192

Abstract

The generation of single-stranded DNA (ssDNA) molecules plays a key role in the SELEX (Systematic Evolution of Ligands by EXponential enrichment) combinatorial chemistry process and numerous molecular biology techniques and applications, such as DNA sequencing, single-nucleotide polymorphism (SNP) analysis, DNA chips, DNA single-strand conformation polymorphism (SSCP) analysis and many other techniques. The purity and yield of ssDNA can affect the success of each application. This study compares the two ssDNA production methods, the strand separation by streptavidin-coated magnetic beads and alkaline denaturation and the lambda exonuclease digestion, in regard to the purity of generated ssDNA and the efficiency. Here, we demonstrate the considerable benefits of ssDNA production by lambda exonuclease digestion for in vitro selection of DNA aptamers. We believe that the generation of ssDNA aptamers using this method will greatly improve the success rate of SELEX experiments concerning the recovery of target-specific aptamers. Full article

(This article belongs to the Special Issue Combinatorial Chemistry)

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164 KiB

Open AccessArticle

The Use of MoStBioDat for Rapid Screening of Molecular Diversity

by Andrzej Bak, Jaroslaw Polanski and Agata Kurczyk

Molecules 2009, 14(9), 3436-3445; https://doi.org/10.3390/molecules14093436 - 8 Sep 2009

Cited by 6 | Viewed by 9261

Abstract

MoStBioDat is a uniform data storage and extraction system with an extensive array of tools for structural similarity measures and pattern matching which is essential to facilitate the drug discovery process. Structure-based database screening has recently become a common and efficient technique in early stages of the drug development, shifting the emphasis from rational drug design into the probability domain of more or less random discovery. The virtual ligand screening (VLS), an approach based on high-throughput flexible docking, samples a virtually infinite molecular diversity of chemical libraries increasing the concentration of molecules with high binding affinity. The rapid process of subsequent examination of a large number of molecules in order to optimize the molecular diversity is an attractive alternative to the traditional methods of lead discovery. This paper presents the application of the MoStBioDat package not only as a data management platform but mainly in substructure searching. In particular, examples of the applications of MoStBioDat are discussed and analyzed. Full article

(This article belongs to the Special Issue Combinatorial Chemistry)

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