No abstract

Selective inhibition is a key focus in the design of chemotherapeutic compounds that can abrogate the oncogenic activities of anti-apoptotic Bcl-2 proteins. Although recent efforts have led to the development of highly selective BH3 mimetics, setbacks such as toxicities have limited their use in cancer therapy. Epigallocatechingallate (EGCG) has been widely reported to selectively inhibit Bcl-2 and Bcl-xL compared to other green tea phenols due to its gallate group. Herein, we investigate the interaction dynamics of EGCG at the hydrophobic grooves of Bcl-2 and Bcl-xL and the consequential effects on their BH4 domains. Arg143 and Asp108 (Bcl-2), and Glu96 and Tyr195 (Bcl-xL) formed high-affinity hydrogen interactions with the gallate group while non-gallate groups of EGCG formed weak interactions. EGCG-bound proteins showed systemic perturbations of BH4 domains coupled with the burial of crucial surface-exposed residues such as Lys17 (Bcl-2) and Asp11 (Bcl-xL); hence, a distortion of non-canonical domain interactions. Interactions of gallate group of EGCG with key hydrophobic groove residues underlie EGCG selectivity while concurrent BH4 domain perturbations potentiate EGCG inhibitory activities. Findings will aid the optimization and design of selective inhibitors that could suppress anti-apoptotic activities of Bcl2-family proteins with minimal toxicities.

This study provides the first account of the molecular impact of UM-164 binding on lyn protein using various computational approaches.

Allosteric binding of IBE-667, activated LFA-1 integrin as evidenced by residual motion at the MIDAS region which appears to be synergistically coordinated by the downward pull of the α7 helix.

Combretum micranthum is used traditionally for many therapeutic purposes such as fatigue, liver ailments, headache, convalescence, blood disease, weight loss among others. Studies suggested that free radical production may be one main reason behind stress induces neurochemical changes that include neurotransmitter imbalance and histopathological alterations in the brain cell. Thus this study examined the relationship between brain histopathological alterations and neurotransmitter imbalance (gamma aminobutyric acid - GABA) in lead exposure, and possible neuroprotective role of Combretum micranthum  methanol leaf extract in mice. Thirty six (36) Swiss Albino mice (19 - 22g body weight) were used for the study, randomized equally into six groups and treated for the period 14days:  a) Normal Control (Distilled water), b) Negative control (40 mg/kg lead acetate), c) lead acetate + 100 mg/kg b.w. extract, d) lead acetate + 50 mg/kg b.w. extract,  e) lead acetate + 25 mg/kg b.w. extract and f) positive control (lead acetate + diazepam 0.5 mg/kg b.w). The study assayed for protective potential of Combretum micranthum on neuronal cell membrane through determination of the brain cells malondialdyhyde (MDA) levels, morphology and GABA levels. Result of the study showed a significantly increase level of GABA in the brain of mice administered doses of the extract with a decreased level of MDA, as compared to those mice treated with 40 mg/kg lead acetate alone, which showed decreased level in GABA (310.83pg/ml), but an increased level of MDA (30.03μmolTBARS/mg). Also the mice administered doses of the extract showed normal neurons while intensive neuronal necrosis was observed on those mice treated with 40mg/kg lead acetate alone. However, mice administered with the doses of the extract shows no any significant difference with those in the normal control and positive control treatment groups.  Also the Combretum micranthum  methanol leaf extract was found, using GC-MS, to contain propargylamine, a compound known to possess anti-apoptosis functions, and also those with GABAergic functions 3,4-dichlorophenylhydrazine, guanidine and aminooxyacetic acid. Findings of the present study has proven Combretum micranthum to be a potential plant in managing and preventing brain structural damage induced by lead administration. Keywords: Lead, Combretum micranthum, GABA, malondialdyhyde (MDA) and histopathology