Detailed (gas-phase) MP2/6-31G*(0.25) potential energy surface scans and CCSD(T) calculations at the complete basis set (CBS) limit were used to analyze (face-to-face) stacking (edge-to-face) T-shaped interactions between histidine (modeled as imidazole) DNA nucleobases. For first time, a variety of relative monomer arrangements both neutral protonated natural nucleobases considered determine effects charge on optimum dimer geometry binding strength. Our results reveal that protonation...

The (gas-phase) MP2/6-31G*(0.25) π···π stacking interactions between the five natural bases and aromatic amino acids calculated using (truncated) monomers composed of conjugated rings and/or (extended) containing biological backbone (either protein or deoxyribose sugar) were previously compared. Although preliminary energetic results indicated that strengthens, while sugar either strengthens weakens, interaction truncated models, reasons for these effects unknown. present work explains...

The ability of a dinucleoside monophosphate to mimic the conformation B-DNA was tested using combination different phosphate models (anionic, neutral, counterion), environments (gas, water), and density functionals (B3LYP, MPWB1K, M06-2X) with 6-31G(d,p) basis set. Three sequences (5′-GXPy-3′, where XPy = T, U or BrU) were considered, which vary in (natural modified) 3′ pyrimidine nucleobase (XPy). These bases selected due their presence natural DNA, structural similarity T and/or...

Laulimalide, a cancer chemotherapeutic in preclinical development, has unique binding site located on two adjacent β-tubulin units between tubulin protofilaments of microtubule. Our extended protein model more accurately mimics the microtubule environment, and together with 135 ns molecular dynamics simulation, identifies new mode for laulimalide, which differs from modes presented work using smaller models. The laulimalide-residue interactions that are computationally revealed explain...

The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules. Despite clinical success of these agents, mechanism action this class drugs remains elusive, making rational design difficult. Molecular dynamics simulations three with αβ-tubulin heterodimer examine similarities differences effects on tubulin, probing both local allosteric effects. their structural similarity, adopt different conformations binding site β-tubulin. similarly...

The emerging field of bioelectricity has revealed numerous new roles for ion channels beyond the nervous system, which can be exploited applications in regenerative medicine. Developing such biomedical interventions birth defects, cancer, traumatic injury, and bioengineering first requires knowledge channel targets expressed tissues interest. This information then used to select combinations small molecule inhibitors and/or activators that manipulate bioelectric state. Here, we provide an...

Previous computational studies have examined pi-pi and pi(+)-pi stacking T-shaped interactions in nucleobase-amino acid dimers, yet it is important to investigate how additional amino acids affect these since simultaneous contacts often appear nature. Therefore, this paper investigates the geometries binding strengths of acid-nucleobase-amino trimers, which are compared corresponding dimer interactions. We concentrate on systems containing natural nucleobase adenine or its (cationic) damaged...

The pi-pi stacking (face-to-face) interactions between the five natural DNA or RNA nucleobases and four aromatic amino acids were compared using three different types of dimers: (1) a truncated nucleoside (nucleobase) stacked with acid; (2) an extended (3) (extended nucleobase) acid. Systematic (MP2/6-31G*(0.25)) potential energy surface scans reveal important information about effects deoxyribose sugar protein backbone on structure binding nucleobase acid models that are typically...

Changes in the magnitude of (M06-2X/6-31+G(d,p)) π-π stacking and T-shaped (nucleobase-edge amino acid-edge) interactions between (neutral or protonated) histidine (His) adenine (A) dimers upon microsolvation with up to four discrete water molecules were determined. A variety histidine-water considered including conventional (N-H···O, N···H-O, C-H···O) hydrogen bonding nonconventional (X-H···π His) lone-pair···π (protonated His)) contacts. Overall, effects His-H(2)O on neutral...

Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA site located between tubulin protofilaments, therefore contact with two adjacent -tubulin units. Here, an improved model mode microtubules presented, using newly available crystal structure pose extended heterodimer complex, as well molecular dynamics simulations. With model, series...

Noscapine, a naturally occurring opium alkaloid, is widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led the development of many noscapine analogues. In this paper we report on synthesis testing novel analogue. Cytotoxicity assessed by MTT colorimetric assay using SKBR-3 paclitaxel-resistant breast cancer cell lines different concentrations for both compound. Microtubule polymerization determine effect new...

Bulky DNA addition products (adducts) formed through attack at the C8 site of guanine can adopt syn orientation about glycosidic bond due to changes in conformational stability or hydrogen-bonding preferences directly arising from bulky group. Indeed, substituent may improve (non-native) Hoogsteen pairs. Therefore, such adducts often result mutations upon replication. This work examines hydrogen-bonded pairs between Watson−Crick and faces ortho para C8-phenoxyl-2′-deoxyguanosine adduct each...

The formation and structure of the 5'-G[8-5]U-3' intrastrand cross-link are studied using density functional theory molecular dynamics simulations due to potential role this lesion in activity 5-halouracils antitumor therapies. Upon UV irradiation 5-halouracil-containing DNA, a guanine radical cation reacts with uracil form cross-link, which involves phosphorescence or an intersystem crossing rate-determining step bond formation. Following ionizing radiation, react, rate-limiting involving...

Background/Aims: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events can be regulated by oxidation of the catalytic domain cysteine residue. Peracids highly oxidizing compounds, thus may induce inactivation PTPs. The aim present study was to evaluate inhibitory effect peracids with different length hydrocarbon chain on activity selected Methods: enzymatic human CD45, PTP1B, LAR, bacterial YopH assayed under cell-free conditions,...

Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives paclitaxel designed bind differentially depending on isotype β-tubulin. Since β-tubulin isotypes have tissue-dependent expression—specifically, βIII is very abundant aggressive tumors and much less common normal tissues—this expected lead tubulin targeted drugs that are more efficacious side effects. Seven were four these amenable synthesis...

Four uracil-containing intrastrand cross-links have been detected in human cells upon UV irradiation of 5-bromouracil-containing DNA, namely 5'-G[8-5]U-3', 5'-U[5-8]G-3', 5'-A[8-5]U-3', and 5'-A[2-5]U-3'. These lesions feature unique composition connectivity compared with other reported the literature. For first time, structural information obtained using molecular dynamics (MD) simulations reveal that all four distort DNA helix, which can involve an extrahelical location cross-link, changes...

This paper reports on the results of chemical synthesis and biological assays performed several new analogues noscapine. We have successfully synthesized four noscapine called 1a–4a, as well their corresponding enantiomers 1b–4b. The pathway consisted three steps with yields in excess 60% each step. Subsequently, we activity intended to reveal mode action these compounds microtubules buffer cancer cell lines. assayed fluorescence quenching effects microtubule polymerization experiments,...