Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants Using In Silico

Current combination therapy of PEG-INF and ribavirin against the Hepatitis C Virus (HCV) genotype-1 infections is ineffective in maintaining sustained viral response in 50% of the infection cases. New compounds in the form of protease inhibitors can complement the combination therapy. Asunaprevir is new to the drug regiment as the NS3-4A protease inhibitor, but it is susceptible to two mutations, namely, R155K and D168A in the protein. Thus, in our study, we sought to evaluate Andrographolide, a labdane-diterpenoid from the Andrographis paniculata plant as an effective compound for inhibiting the NS3-4A protease as well as its concomitant drug-resistant mutants by using molecular docking and dynamic simulations. Our study shows that Andrographolide has best docking scores of −15.0862, −15.2322, and −13.9072 compared to those of Asunaprevir −3.7159, −2.6431, and −5.4149 with wild-type R155K and D168A mutants, respectively. Also, as shown in the MD simulations, the compound was good in binding the target proteins and maintains strong bonds causing very less to negligible perturbation in the protein backbone structures. Our results validate the susceptibility of Asunaprevir to protein variants as seen from our docking studies and trajectory period analysis. Therefore, from our study, we hope to add one more option in the drug regiment to tackle drug resistance in HCV infections

Structure Prediction and Active Site Analysis of New H1N1 Neuraminidase:Target for Antiviral Drug Design

Abstract: The H1N1 viral envelope protein neuraminidase encoded by NA gene plays a key role in the pathogenesis of swine flu. The active site of the neuraminidase protein is targeted by presently available antiviral drugs. The influenza virus often proves to be resistant to currently available drugs, due single amino acid substitutions conferred by the mutations in the gene coding for neuraminidase protein. The latest Influenza A virus A/Perth/262/2009(H1N1) sequence with accession number ADJ67981 was selected from NCBI. The BLAST program was used to identify the best template structure, which was found to be 3NSS_A. Sequence alignment was carried out with the template and query sequence, the identity and similarity was found to be 81.9% and 82.6% respectively. Homology modeling was performed using Accelrys Discovery Studio 3.5 software, the model with the lowest energy was then assessed for stereochemical quality and side-chain environment. The PDF energy and DOPE score of the best modeled structure was 2090.1682 and -43752.3632 respectively. Further active site optimization of the modeled protein was performed by molecular dynamics. The key active site residues which are crucial for further docking studies were ascertained

PHARMACOPHORE ELUCIDATION AND DOCKING STUDIES ON ANTI-INFLAMMATORY COMPOUNDS OF MEDICINAL PLANTS FOR ULCERATIVE COLITIS

ABSTRACT Inflammatory bowel diseases such as Ulcerative Colitis (UC) are becoming common in this aging society throughout the world which includes formation of ulcers or open sores. Since, there is no known medical cure for UC; the therapeutic armamentarium is aimed at reducing the signs and symptoms associated with the disorder. The role of antibiotics in the treatment of severe active UC is controversialbecause the clinically used anti-inflammatory drugs suffer from the disadvantage of side effects and high cost of treatment. In the present study, NF-kB p50/p65 is docked in two different ways, one with the glucocorticoid receptor protein using ZDOCK in Accelrys Discovery Studio 3.5 and the other is screening and docking of400 anti-inflammatory natural compounds derived from plant source which offer a great hope in the identification of lead compounds.These compounds were investigated for their inhibitory activity by molecular docking studies and ADME/T properties of the compounds were analyzed for drug like candidates by using the commercial software's Accelrys Discovery Studio, Lead-IT and GOLD 5.1. Based on the docking results and toxicity analysis using TOPKAT, the best compounds determined are Ginkgetin, Bilobetin and Mesuaxanthone_B. The Pharmacophore studies have also shown that these compounds are having very less side effects and further investigations are requiredto take into clinical trials.  KEYWORDS: Inflammatory bowel disease, NF-kB p50/p65, Glucocorticoid, ZDOCK, TOPKAT Â

Association of genetic polymorphisms of claudin-1 with small vessel vascular dementia

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood-brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin-1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case-control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin-1 genotyping, were analysed by real-time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01)

Prediction of deleterious single nucleotide polymorphisms and their effect on the sequence and structure of the human CCND1 gene

أهداف البحث: إن الجين CCND1 المعبر للبروتين G١/S-السيكلين المحدد٬ والمنظم لانتقاله في دورة الخلية يثبط أيضا البروتينات في الأورام الأرومية الشبكية. وزيادة التعبير أو إعادة التنظيم في هذا الجين قد تؤدي إلى أورام مختلفة. تهدف هذه الدراسة لتحديد الأضرار الممكنة غير المترادفة من النيوكليوتيد الوحيد المتعدد الأشكال للجين CCND1 باستخدام الطرق الحاسوبية. طرق البحث: تم استعادة النيوكليوتيد الوحيد المتعدد الأشكال في جينات الإنسان CCND1 من قاعدة معلومات النيوكليدات الوحيدة المتعددة الأشكال. تم فحص هذه النيوكليوتيدات الوحيدة المتعددة الأشكال بواسطة فرز عدم الاحتمال من الاحتمال والتنبؤ بخوادم النيوكليوتيدات الوحيدة المتعددة الأشكال. كما تم بناء الطفرات التي تحوي النيوكليوتيدات الوحيدة المتعددة الأشكال الضارة باستخدام استديو الاكتشاف ٥٬٣ وأجريت الدراسات الديناميكية على أصناف محلية وطافرة. النتائج: تم العثور على ١١٩٤ من النيوكليوتيدات الوحيدة المتعددة الأشكال في الإنسان٬ منها ٩٤ مغلطة و٢ لا قيمة لها. كما وُجدت ثلاث نيوكليوتيدات وحيدة متعددة الأشكال ضارة. وأظهرت الدنياميكيات الجزيئية وتحليل المسار انحرافا كبيرا في قيم متوسط جذر الانحراف التربيعي في الطفرة N٢١٦K من قيم البروتين المحلي. الاستنتاجات: استنادا على هذه الدراسة٬ نقترح أن النيوكليوتيدات الوحيدة المتعددة الأشكال مع تعريفها ل rs١١٢٥٢٥٠٩٧ NM_٠٥٣٠٥٦.٢:c.٦٤٨C>G)) قد تسبب انحرافات في جين CCND 1٬ التي قد تؤدي بالتالي إلى تغيرات في وظائف البروتين G١/S-السيكلين المحدد. وهذا٬ بالمقابل يمكن أن يكون السبب في حدوث سرطان الدم النخاعي الحاد

Outcomes of patients with severe tricuspid regurgitation and congestive heart failure

Objectives A substantial number of patients with severe tricuspid regurgitation (TR) and congestive heart failure (CHF) are medically managed without undergoing corrective surgery. We sought to assess the characteristics and outcomes of CHF patients who underwent tricuspid valve surgery (TVS), compared with those who did not. Methods Retrospective observational study involving 2556 consecutive patients with severe TR from the Cleveland Clinic Echocardiographic Database. Cardiac transplant patients or those without CHF were excluded. Survival difference between patients who were medically managed versus those who underwent TVS was compared using Kaplan-Meier survival curves. Multivariate analysis was performed to identify variables associated with poor outcomes. Results Among a total of 534 patients with severe TR and CHF, only 55 (10.3%) patients underwent TVS. Among the non-surgical patients (n=479), 30% (n=143) had an identifiable indication for TVS. At 38 months, patients who underwent TVS had better survival than those who were medically managed (62% vs 35%; p<0.001). On multivariate analysis, advancing age (HR: 1.23; 95% CI 1.12 to 1.35 per 10-year increase in age), moderate (HR: 1.39; 95% CI 1.01 to 1.90) and severe (HR: 2; 95% CI 1.40 to 2.80) right ventricular dysfunction were associated with higher mortality. TVS was associated with lower mortality (HR: 0.44; 95% CI 0.27 to 0.71). Conclusion Although corrective TVS is associated with better outcomes in patients with severe TR and CHF, a substantial number of them continue to be medically managed. However, since the reasons for patients not being referred to surgery could not be ascertained, further randomised studies are needed to validate our findings before clinicians can consider surgical referral for these patients.Revisión por pare

In silico molecular docking analysis of karanjin against alzheimer’s and parkinson’s diseases as a potential natural lead molecule for new drug design, development and therapy

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that have emerged as among the serious health problems of the 21st century. The medications currently available to treat AD and PD have limited efficacy and are associated with side effects. Natural products are one of the most vital and conservative sources of medicines for treating neurological problems. Karanjin is a furanoflavonoid, isolated mainly from Pongamia pinnata with several medicinal plants, and has been reported for numerous health benefits. However, the effect of karanjin on AD and PD has not yet been systematically investigated. To evaluate the neuroprotective effect of karanjin, extensive in silico studies starting with molecular docking against five putative targets for AD and four targets for PD were conducted. The findings were compared with three standard drugs using Auto Dock 4.1 and Molegro Virtual Docker software. Additionally, the physiochemical properties (Lipinski rule of five), drug-likeness and parameters including absorption, distribution, metabolism, elimination and toxicity (ADMET) profiles of karanjin were also studied. The molecular dynamics (MD) simulations were performed with two selective karanjin docking complexes to analyze the dynamic behaviors and binding free energy at 100 ns time scale. In addition, frontier molecular orbitals (FMOs) and density-functional theory (DFT) were also investigated from computational quantum mechanism perspectives using the Avogadro-ORCA 1.2.0 platform. Karanjin complies with all five of Lipinski’s drug-likeness rules with suitable ADMET profiles for therapeutic use. The docking scores (kcal/mol) showed comparatively higher potency against AD and PD associated targets than currently used standard drugs. Overall, the potential binding affinity from molecular docking, static thermodynamics feature from MD-simulation and other multiparametric drug-ability profiles suggest that karanjin could be considered as a suitable therapeutic lead for AD and PD treatment. Furthermore, the present results were strongly correlated with the earlier study on karanjin in an Alzheimer’s animal model. However, necessary in vivo studies, clinical trials, bioavailability, permeability and safe dose administration, etc. must be required to use karanjin as a potential drug against AD and PD treatment, where the in silico results are more helpful to accelerate the drug development