Minichromosome maintenance complex component 7 (MCM7) belongs to the minichromosome maintenance family that is important for the initiation of eukaryotic DNA replication. Overexpression of the MCM7 protein is relative to cellular proliferation and responsible for aggressive malignancy in various cancers. Mechanistically, inhibition of MCM7 significantly reduces the cellular proliferation associated with cancer. To date, no effective small molecular candidate has been identified that can block the progression of cancer induced by the MCM7 protein. Therefore, the study has been designed to identify small molecular-like natural drug candidates against aggressive malignancy associated with various cancers by targeting MCM7 protein. To identify potential compounds against the targeted protein a comprehensive in silico drug design including molecular docking, ADME (Absorption, Distribution, Metabolism and Excretion), toxicity, and molecular dynamics (MD) simulation approaches has been applied. Seventy phytochemicals isolated from the neem tree (Azadiractha indica) were retrieved and screened against MCM7 protein by using the molecular docking simulation method, where the top four compounds have been chosen for further evaluation based on their binding affinities. Analysis of ADME and toxicity properties reveals the efficacy and safety of the selected four compounds. To validate the stability of the protein–ligand complex structure MD simulations approach has also been performed to the protein–ligand complex structure, which confirmed the stability of the selected three compounds including CAS ID:105377-74-0, CID:12308716 and CID:10505484 to the binding site of the protein. In the study, a comprehensive data screening process has performed based on the docking, ADMET properties, and MD simulation approaches, which found a good value of the selected four compounds against the targeted MCM7 protein and indicates as a promising and effective human anticancer agent.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

Chronic Hepatitis C virus has the potential of inducing insulin resistance and type 2 Diabetes Mellitus in vitro as well as in vivo . Structural and non-structural proteins of HCV modulate cellular gene expression in such a way that insulin signaling is hampered, concomitantly leads toward diabetes mellitus. A number of mechanisms have been proposed in regard to the HCV induced insulin resistance involving the upregulation of Inflammatory cytokine TNF-α, hypophosphorylation of IRS-1 and IRS-2, phosphorylation of Akt, up-regulation of gluconeogenic genes, accumulation of lipids and targeting lipid storage organelles. This review provides an insight of molecular mechanisms by which HCV structural and non-structural proteins can induce insulin resistance.

BackgroundHepatitis B virus (HBV) infections play an important role in the development of hepatocellular carcinoma (HCC). HBV X protein (HBx) is a multifunctional protein that can modulate various cellular processes and plays a crucial role in the pathogenesis of HCC. HBx is known to interact with DNA helicase components of TFIIH, a basal transcriptional factor and an integral component of DNA excision repair.ResultsIn this study, the functional relevance of this association was further investigated in the context to DNA repair. By site-directed mutagenesis HBx's critical residues for interaction with TFIIH were identified. Similarly, TFIIH mutants lacking ATPase domain and the conserved carboxyl-terminal domain failed to interact with HBx. Yeast and mammalian cells expressing HBxwt conferred hypersensitivity to UV irradiation, which is interpreted as a basic deficiency in nucleotide excision repair. HBxmut120 (Glu to Val) was defective in binding to TFIIH and failed to respond to UV.ConclusionsWe conclude that HBx may act as the promoting factor by inhibiting DNA repair causing DNA damage and accumulation of errors, thereby contributing to HCC development.

Background: Due to the inherently unstable nature of HCV, various genotypes have been identified. Steatosis is a histological feature in the progression of HCV-associated liver disease and has been shown to alter the host lipid metabolism. Objective: Assess the distribution of HCV genotypes in the two provinces of Pakistan, and determine the association of hepatic steatosis with altered clinical and virological factors in chronic HCV patients. Methods: One hundred twenty six chronic HCV patients (steatosis in 49 patients) were enrolled for qualitative analysis by PCR. Out of 126 ELISA and PCR positive samples, 119 (48 with hepatic steatosis) chronic HCV patients (mean age 42.0±13.3 years, mean body mass index (BMI) 24.2±4.1) were proved positive after PCR-based detection. Biochemical and virological factors such as HCV genotype, or glucose, in 119 CHC patients were determined and compared between patients with and without hepatic steatosis. Results: Out of 126 samples, 119 were HCV positive, where 58 (48.7%) were genotype 3a, 24 (20.2%) were 3b, 12 (10.1%) were 1a, eight (6.7%) were 2a, six (5.0%) were 1b, and one (0.8%) was 4. Furthermore, seven (5.9%) had a co-infection and three (2.5%) were untypable. BMI (p=0.004), genotype 3a (p<0.001), and triglycerides (p=0.002) were significantly associated with steatosis. It is noteworthy that cholesterol (p=0.281), glucose (p=0.305), lowdensity lipoprotein (p=0.101), high-density lipoprotein (p=0.129), alanine amino transferase (p=0.099), aspartate transaminase (p=0.177), bilirubin (p= 0.882), and age (p=0.846) showed non-significant association. Conclusion: Genotype 3a is the predominant genotype in Pakistan. Hepatic steatosis is quite frequent feature in HCV patients and strongly correlates with BMI, genotype 3a, and triglyceride contents in patients infected with HCV.