Proposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studies

The mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53-suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high-throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all-atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds (E1-E11) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds (E1,E2,E5,E6,E9, andE11) in breast cancer cell lines and six compounds (E1,E2,E5,E6,E8, andE10) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis.WOS:0005503426000042-s2.0-85088278516PubMed: 3269196

Controlled release of imatinib mesylate from PLGA microspheres inhibit craniopharyngioma mediated angiogenesis

Poly(lactic-co-glycolic acid) microspheres loaded with imatinib mesylate has been developed as a new therapeutic strategy to prevent craniopharyngioma recurrence. Microspheres composed of different lactic/glycolic acid ratios, molecular weights and drug compositions were synthesized and loaded with imatinib mesylate by modified double-emulsion/solvent evaporation technique and subsequently characterized by particle-size distribution, scanning electron microscopy, encapsulation efficiency and in vitro drug release. Inhibitory potential of imatinib containing microspheres on tumor neovascularization was investigated on craniopharyngioma tumor samples by rat cornea angiogenesis assay. Results showed that microspheres in different LA:GA ratios [LA:GA 50:50 (G50), 75:25 (G25), 85:15 (G15)] considerably reduced neovascularization induced by recurrent tumor samples in an in vivo angiogenesis assay (P < 0.01). Our data indicate that local delivery of imatinib mesylate to the post-surgical tumoral cavity using biodegradable microspheres may be a promising biologically selective approach to prevent the recurrence of craniopharyngiomas, via inhibition of neovascularization

In vivo effect of pregnancy on angiogenesis potential of arteriovenous malformation tissue samples: an experimental study

CONCLUSIONS: Findings of this study suggest that angiogenic activity of AVM tissues may increase during late pregnancy, hence physicians should inform pregnant patients with AVM of the potential risk

Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis

Background: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers

CSF Proteomics Identifies Specific and Shared Pathways for Multiple Sclerosis Clinical Subtypes.

Multiple sclerosis (MS) is an immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) with a heterogeneous clinical presentation and course. There is a remarkable phenotypic heterogeneity in MS, and the molecular mechanisms underlying it remain unknown. We aimed to investigate further the etiopathogenesis related molecular pathways in subclinical types of MS using proteomic and bioinformatics approaches in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS (n=179). Comparison of disease groups with controls revealed a total of 151 proteins that are differentially expressed in clinically different MS subtypes. KEGG analysis using PANOGA tool revealed the disease related pathways including aldosterone-regulated sodium reabsorption (p=8.02x10(-5)) which is important in the immune cell migration, renin-angiotensin (p=6.88x10(-5)) system that induces Th17 dependent immunity, notch signaling (p=1.83x10(-10)) pathway indicating the activated remyelination and vitamin digestion and absorption pathways (p=1.73x10(-5)). An emerging theme from our studies is that whilst all MS clinical forms share common biological pathways, there are also clinical subtypes specific and pathophysiology related pathways which may have further therapeutic implications

Development of imidazolone based angiotensin II receptor type I inhibitor small molecule as a chemotherapeutic agent for cell cycle inhibition

Cell cycle inhibitors are considered as hallmark strategy for cancer treatment due to their relatively higher selectivity and efficacy on various cancer types in comparison to cytotoxic agents. Small molecules target dividing cells in G1/S, G2 or M phases of cells to arrest and eventually trigger cancer cells to enter apoptosis and/or inhibit tumor growth. Cell cycle arrest at G2/M phase is a widely used approach to inhibit proliferating cancer cells. We report a novel angiotensin II receptor type I (AT1R) antagonist that also targets CDC2 (CDK1) kinase thereby showing a putative anti-cancer activity. The molecule named 19D was tested in various cancer cell lines at different concentrations. Molecular mechanisms of action triggered by the treatment of 19D were investigated for anti-cancer activity at cellular and molecular level. 19D molecule showed a potent cell cycle arrest with anti-proliferation activity. Cells treated with 19D showed nuclear deteriorations and apoptotic induction on cancer cells. Moreover, the mechanism of cell cycle inhibition was revealed as G2/M arrest via suppressing the CDC2 kinase cell cycle check point inhibitor. In conclusion, 19D (an AT1R antagonist) is a novel small molecule/imidazolone derivative which has been demonstrated as a fairly potent anti-cancer molecule

Prospective outcome analysis of multiple sclerosis cases reveals candidate prognostic cerebrospinal fluid markers

Background Predicting the long-term disability outcomes of multiple sclerosis (MS) cases is challenging. Objective We prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up. Methods Patients with regular follow-up visits were assigned into two groups: those with an age-related MS severity (ARMSS) score ≥5 (unfavourable course group, N = 27) and ARMSS score Results CSF alpha-2-macroglobulin (P = 0.0015), apo-A1 (P = 0.0016), and haptoglobin (P = 0.0003) protein levels, as well as cerebral lesion load (>9 lesions) on magnetic resonance imaging, gait disturbance (P = 0.04), and bladder/bowel symptoms (P = 0.01) were significantly higher in the unfavourable course group than in the favourable course group. Optic nerve involvement evident on initial magnetic resonance imaging (P = 0.002) and optic neuritis (P = 0.01) were more frequent in the favourable course group. Conclusion The herein identified initial CSF protein levels, in addition to the clinical and radiological parameters at disease onset, have predictive value for long-term disability in MS cases

Prospective outcome analysis of multiple sclerosis cases reveals candidate prognostic cerebrospinal fluid markers.

BackgroundPredicting the long-term disability outcomes of multiple sclerosis (MS) cases is challenging.ObjectiveWe prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up.MethodsPatients with regular follow-up visits were assigned into two groups: those with an age-related MS severity (ARMSS) score ≥5 (unfavourable course group, N = 27) and ARMSS score ResultsCSF alpha-2-macroglobulin (P = 0.0015), apo-A1 (P = 0.0016), and haptoglobin (P = 0.0003) protein levels, as well as cerebral lesion load (>9 lesions) on magnetic resonance imaging, gait disturbance (P = 0.04), and bladder/bowel symptoms (P = 0.01) were significantly higher in the unfavourable course group than in the favourable course group. Optic nerve involvement evident on initial magnetic resonance imaging (P = 0.002) and optic neuritis (P = 0.01) were more frequent in the favourable course group.ConclusionThe herein identified initial CSF protein levels, in addition to the clinical and radiological parameters at disease onset, have predictive value for long-term disability in MS cases