A PREDICTIVE MODEL FOR ETHNOMEDICINAL DISCOVERY RESEARCH- A NIGERIAN CASE STUDY

Using a model parametrically dependent on a number of research factors we have examined the relationship between ethnomedicinal drug discovery research in Nigeria and the goal of advancing drug candidates into preclinical evaluation. Our investigation covered a 13-year period and involves several ethnomedicinally relevant plant materials. The employed qualitative model utilizes model scores in assessing research quality and the chances to attain preclinical testing. Based on the model, the research methodologies were found to focus on highly rudimentary tools involving crude extraction, which the model indicated as a vital disadvantage. The existence of foreign collaborations as well as the number of such collaborations was found to improve model score and as extension the likelihood to generate candidates for drug development

Isolation of novel para-pentyl phenyl benzoate from Mondia whitei.(Hook.F.) skeels (periplocaceae), its structure, synthesis and neuropharmacological evaluation

Background: Mondia whitei L. (Hook. F.) Skeels (Periplocaceae) is a medicinal plant used locally in managing pain, fever, loss of appetite and as aphrodiasc in the South-Western states of Nigeria. However, the fruit is consumed habitually in the South-Eastern states of Nigeria, leading to speculation that it may possess some central nervous system effect but which has not been scientifically investigated, hence this study.Methodology: Fresh fruits of Mondia whitei were collected and identified by a taxonomist. They were chopped into small pieces and extracted with absolute ethanol. The crude extract was subjected to various chromatographic techniques to isolate a novel compound whose structure was elucidated from the analysis of the crystal data and by extensive use of spectroscopy. The structure was confirmed by synthesis. The compound was subjected to anxiolytic and sedative activity assay. Computational analysis of the receptor binding event of isolated compound at the gamma amino butyric acid A receptor was also evaluated.Results: The structure of the compound was elucidated as para pentyl phenyl benzoate. The neuropharmacological evaluation of the compound indicated significant (p<0.05) depression of the central nervous system. The binding characteristics of the compound to gamma amino butyric acid A receptors appears to be more favorable than those obtained for gamma amino butyric acid, chlorpromazine, benzamidine, and is comparable with the affinity obtained for pentobarbitone and diazepam.Conclusion: These present data provide evidence for the role of para pentyl phenyl benzoate in the habitual consumption of the fruit as well as its central nervous system activities.Keywords: Mondia whitei, Periplocaceae, isolation and synthesis, sedative and anxiolytic effect and Para pentylphenyl benzoat

Isolation of novel para-pentyl phenyl benzoate from Mondia whitei. (Hook.F) Skeels (Periplocaceae), its structure, synthesis, and neuropharamacological evaluation

Background: Mondia whitei L. (Hook. F.) Skeels (Periplocaceae) is a medicinal plant used locally in managing pain, fever, loss of appetite and as aphrodiasc in the South-Western states of Nigeria. However, the fruit is consumed habitually in the South-Eastern states of Nigeria, leading to speculation that it may possess some central nervous system effect but which has not been scientifically investigated, hence this study. Methodology: Fresh fruits of Mondia whitei were collected and identified by a taxonomist. They were chopped into small pieces and extracted with absolute ethanol. The crude extract was subjected to various chromatographic techniques to isolate a novel compound whose structure was elucidated from the analysis of the crystal data and by extensive use of spectroscopy. The structure was confirmed by synthesis. The compound was subjected to anxiolytic and sedative activity assay. Computational analysis of the receptor binding event of isolated compound at the gamma amino butyric acid A receptor was also evaluated. Results: The structure of the compound was elucidated as para pentyl phenyl benzoate. The neuropharmacological evaluation of the compound indicated significant (p<0.05) depression of the central nervous system. The binding characteristics of the compound to gamma amino butyric acid A receptors appears to be more favorable than those obtained for gamma amino butyric acid, chlorpromazine, benzamidine, and is comparable with the affinity obtained for pentobarbitone and diazepam. Conclusion These present data provide evidence for the role of para pentyl phenyl benzoate in the habitual consumption of the fruit as well as its central nervous system activities

ISOLATION OF NOVEL PARA-PENTYL PHENYL BENZOATE FROM MONDIA WHITEI.(HOOK.F.) SKEELS (PERIPLOCACEAE), ITS STRUCTURE, SYNTHESIS AND NEUROPHARMACOLOGICAL EVALUATION.

Background: Mondia whitei L. (Hook. F.) Skeels (Periplocaceae) is a medicinal plant used locally in managing pain, fever, loss of appetite and as aphrodiasc in the South-Western states of Nigeria. However, the fruit is consumed habitually in the South-Eastern states of Nigeria, leading to speculation that it may possess some central nervous system effect but which has not been scientifically investigated, hence this study. Methodology: Fresh fruits of Mondia whitei were collected and identified by a taxonomist. They were chopped into small pieces and extracted with absolute ethanol. The crude extract was subjected to various chromatographic techniques to isolate a novel compound whose structure was elucidated from the analysis of the crystal data and by extensive use of spectroscopy. The structure was confirmed by synthesis. The compound was subjected to anxiolytic and sedative activity assay. Computational analysis of the receptor binding event of isolated compound at the gamma amino butyric acid A receptor was also evaluated. Results: The structure of the compound was elucidated as para pentyl phenyl benzoate. The neuropharmacological evaluation of the compound indicated significant (

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the &beta;-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30&ndash;40 years ago up to more promising 12- and 15-mers under consideration in recent years

Investigation of the interaction between Alzheimer's abeta peptide and aggregation inhibitors using molecular simulations

Protein misfolding has long been known to constitute an important class of disease initiating factors. Of special significance in this group is Alzheimers disease (AD) in which the aggregation of misfolded small molecular weight amyloid ß peptides (Aß) triggers a host of biochemical anomalies that destroy brain neuronal processes. However, in spite of the enormous efforts invested into AD research over the past one century, it has remained without a cure. The available drugs only offer symptomatic relief without improving the associated neurological decline and the typically poor prognosis. The absence of a cure largely results from the peculiarities of the Aß peptide, the molecular principle commonly targeted for drug development. Aß is produced via post-translational cleavage of the transmembrane amyloid precursor protein followed by its release into the extracellular medium. Unlike most other protein drug targets however, Aß both lacks a regular three dimensional fold and possesses a significantly high aggregation propensity under physiological conditions. Aß’s extremely high aggregation tendency renders most available experimental structure determination tools, to a large extent, unable to determine its physiological conformations. Attempts to address this challenge includes the use of nonphysiological solubilising conditions, which at the same time compromises the usefulness of such models for Aß-directed drug discovery. Molecular simulations provide a veritable tool for circumventing this challenge and have been employed in this thesis. In this thesis, a number of molecular simulation techniques have been employed in studying and describing the structural dynamics of the two physiologically dominant Aß species–Aß40 and Aß42. Multiple molecular dynamics (MD) simulations on microsecond time scale were used to study Aß40 and Aß42 monomers in explicit water and under simulation conditions mimicking physiological conditions. To validate the obtained results, we employed chemical shift calculations which we compared with Nuclear Magnetic Resonance (NMR) chemical shifts, enabling us identify the force field that correctly models experimentally relevant Aß structural ensembles. We observed Aß42 monomer to form higher ß-sheet structure than Aß40 and provided an explanation for this and other specific aspects of the folding. We also employed atomistic MD simulation in studying the conformational behaviour of Aß42 monomer under four pH conditions and found the peptide net charge to be the single most important factor directing its folding. Our goal for analysing Aß’s conformation is to obtain structural ensembles closely resembling the physiological state, which can be used in investigating Aβ’s interaction with aggregation inhibitors (D-peptides) currently investigated in the group of Prof. Dr. Willbold (Institute of Complex Systems Forschungszentrum, Jülich) for their anti-amyloid activities against Aß. The inhibitors abolished Aß’s toxicity in a dose-dependent manner, but their mechanism(s) of action, to a large extent, remains unknown. In this work, we present the outcome of the molecular simulations performed to explain the possible mechanism of action of the D-peptides. Our analyses reveal the D-peptides as interacting with both Aß42 monomer and pentamer via strong electrostatic attraction and destroying its ß-sheets. We also performed exhaustive point mutations on the D-peptides’ sequences using both natural and non-natural amino acids. Our results suggest possible modifications that may be performed on the original D-peptides’ amino acid sequences that can help modify their selectivity for different Aß oligomer sizes. Based on these results we propose possible changes to the original D-peptide sequences, and their binding selectivity for different Aß oligomer will be tested in future experiments

Topology and parameter data of thirteen non-natural amino acids for molecular simulations with CHARMM22

In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM) calculations involving geometry optimization and potential energy surface scanning at the HF 6-31G(d) and HF 6-311G(d,p) levels of theory. The resulting energy data points were fitted to mathematical functions representing each component of the CHARMM22 force field. Further fine-tuning of the parameters utilized molecular mechanics energies, which were iteratively calculated and compared to the corresponding QM values until the latter were satisfactorily reproduced. The final force field data were validated with molecular dynamics simulations in explicit solvent conditions

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30–40 years ago up to more promising 12- and 15-mers under consideration in recent years

Early amyloid β-protein aggregation precedes conformational change

The aggregation of amyloid-β protein (1–42) is studied at experimental concentrations using all-atom molecular dynamics simulations. We observe a fast aggregation into oligomers without significant changes in the internal structure of individual proteins. The aggregation process is characterized in terms of transition networks

The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility