A Molecular Dynamics Study of Lunasin

Lunasin, a 43 amino acid peptide, suppresses chemically induced transformations in mammalian cells and skin carcinogenesis in mice. This peptide has also been reported to exhibit very good bioavailability after its oral administration. However, despite its biological and medicinal significance, the exact three-dimensional (3D) structure of lunasin is thus far not yet fully characterized. Thus this work is aimed at exploring the conformational profile of lunasin,using classical molecular dynamics (MD) simulations at the time scale of 300 ns. The results obtained from the MD trajectory reveal that lunasin has a strong propensity to exhibit three characteristic α helical bundles in its structure supported by residues His5-Cys10, Cys22-Ile30 and Asp35-Asp41. The reported cell adhesion motif (Arg-Gly-Asp) of lunasin responsible for its binding to cell chromatin, on other hand, did not exhibit any characteristic secondary feature. The structural information obtained from the current study could be useful to better understand the bioactive conformation of lunasin.Keywords: Lunasin, molecular dynamics, amber, CLASICO, α-helix, β-turn, PTRAJ, RGD, RMS

Alternative Synthesis of 2,4-Substituted-1,3-thiazines and 2,5-Substituted-thiazole Derivatives

Aneasy and convenient route for the synthesis of 2,4-substituted thiazine (3–6) and 2,5-substituted thiazole (16) derivatives from phenacetamidines and glycine methyl ester is reported. To the best of our knowledge, this is the first report in which phenacetamidines have been utilized as precursors for thiazine synthesis. The syntheses of novel cyclic fused 1,3-diazabutadienes 13 and 2-aza-1,3-butadiene 17, and iodocyclization of 17 leading to the formation of thiazole 16a are also reported. In this paper a total of twenty novel compounds are reported.Keywords: Phenacetamidines, 1,3-thiazines, thiazoles, cyclization

Computer Simulation Studies of Trishomocubane Heptapeptide of the Type Ac-Ala3-Tris-Ala3-NHMe

As part of an extension on the cage peptide chemistry, the present work involves an assessment of the conformational profile of trishomocubane heptapeptide of the type Ac-Ala3-Tris-Ala3-NHMe using molecular dynamics (MD) simulations. All MD protocols were explored within the framework of a molecular mechanics approach using the PARM94 force field parameters modified in-house to mimic the implicit and explicit solvent conditions. The 50 ns MD trajectories revealed a tendency of the trishomocubane polypeptide to adopt bent conformations in vacuo, MEOH and TIP3P solvent models, consistent with previous studies undertaken in our laboratory. The aim of this paper is to exemplify the tendency of the highly constrained cage residues to promote reverse-turn characteristics in the polypeptide chains, which could play a pivotal role in the design of new cagepeptidomimetics.Keywords: Trishomocubane, molecular dynamics, Amber, CLASICO, β-turn, α-helical PDF and supplementary file attached

Computational and Experimental Studies on the Hetero-Diels-Alder Reactions of Cross-conjugated Enaminones with Sulphene

Ab initio and density functional theory (DFT) calculations have been used to investigate the feasibility of cycloaddition reactions of enaminones 1 with sulphene. Specifically, the geometry optimizations, frequency calculations and self-consistent reactionfield (SCRF) solvent simulations in combination with higher-quality relative energies carried out at the DFT level using the 6-31+G(d) basis set suggests that the product obtained is both thermodynamically and kinetically preferred, indicating the feasibility of this reaction. Additionally, experimental studies carried out on the reactions of these enaminones 1 with sulphene were also found to be in agreement with the theoretical predictions resulting in the synthesis of a variety of novel oxathiine derivatives having great biological and medicinal importance.Keywords: Enaminones, cycloadditions, sulphene, DFT, SCRFPDF and Supplementry file attache

Insight into the biosensing of graphene

Graphene oxide, a century old material has attracted the interest of researchers owing to its specific 2D structure and unique electronic, optical, thermal, mechanical and electrochemical properties. The recent advancements in the field of biotechnology and biomedical engineering are targeted at exploring the biosensing applications of graphene oxide due to its biocompatibility. It is considered to be one of the most versatile materials, with wide range of applications which can be tailored by functionalization of the different oxygen containing groups present in the structure. In this review the focus is on the biosensing applications of graphene oxide, detection of analytes with high sensitivity and selectivity. This would give insight into the designing of feasible protocols for the analysis of therapeutic diseases and environmental safety, thereby improving the quality of human life

Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors

[EN] The development and advancement of prostate cancer (PCa) into stage 4, where it metastasize, is a major problem mostly in elder males. The growth of PCa cells is stirred up by androgens and androgen receptor (AR). Therefore, therapeutic strategies such as blocking androgens synthesis and inhibiting AR binding have been explored in recent years. However, recently approved drugs (or in clinical phase) failed in improving the expected survival rates for this metastatic-castration resistant prostate cancer (mCRPC) patients. The selective CYP17A1 inhibition of 17,20-lyase route has emerged as a novel strategy. Such inhibition blocks the production of androgens everywhere they are found in the body. In this work, a three dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore model is developed on a diverse set of non-steroidal inhibitors of CYP17A1 enzyme. Highly active compounds are selected to define a six-point pharmacophore hypothesis with a unique geometrical arrangement fitting the following description: two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two aromatic rings (R). The QSAR model showed adequate predictive statistics. The 3D-QSAR model is further used for database virtual screening of potential inhibitory hit structures. Density functional theory (DFT) optimization provides the electronic properties explaining the reactivity of the hits. Docking simulations discovers hydrogen bonding and hydrophobic interactions as responsible for the binding affinities of hits to the CYP17A1 Protein Data Bank structure. 13 hits from the database search (including five derivatives) are then synthesized in the laboratory as different scaffolds. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in vitro experiments reveals three new chemical entities (NCEs) with half maximal inhibitory concentration (IC50) values against the lyase route at mid-micromolar range with favorable selectivity to the lyase over the hydroxylase route (one of them with null hydroxylase inhibition). Thus, prospective computational design has enabled the design of potential lead lyase-selective inhibitors for further studies.This work research work was supported financially in part by the National Research Foundation of South Africa and First Rand Foundation (UID: 112151). This work was also made possible through funding by the Research Capacity Development Initiative-South African Medical Research Council (RCDI-SAMRC). The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of NRF and SAMRC. 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