Molecular docking and dynamics based approach for the identification of kinase inhibitors targeting PI3Kα against non-small cell lung cancer: a computational study

Non-small cell lung cancer (NSCLC) is an obscure disease whose incidence is increasing worldwide day by day, and PI3Kα is one of the major targets for cell proliferation due to the mutation. Since PI3K is a class of kinase enzyme, and no in silico research has been performed on the inhibition of PI3Kα mutation by small molecules, we have selected the protein kinase inhibitor database and performed the energy minimization process by ligand preparation. The key objective of this research is to identify the potential hits from the protein kinase inhibitor library and further to perform lead optimization by a molecular docking and dynamics approach. And so, the protein was selected (PDB ID: 4JPS), having a unique inhibitor and a specific binding pocket with amino acid residue for the inhibition of kinase activity. After the docking protocol validation, structure-based virtual screening by molecular docking and MMGBSA binding affinity calculations were performed and a total of ten hits were reported. Detailed analysis of the best scoring molecules was performed with ADMET analysis, induced fit docking (IFD) and molecular dynamics (MD) simulation. Two molecules – 6943 and 34100 – were considered lead molecules and showed better results than the PI3K inhibitor Copanlisib in the docking assessment, ADMET analysis, and molecular dynamics simulation. Furthermore, the synthetic accessibility of the two compounds – 6943 and 34100 – was investigated using SwissADME, and the two lead molecules are easier to synthesize than the PI3K inhibitor Copanlisib. Computational drug discovery tools were used for identification of kinase inhibitors as anti-cancer agents for NSCLC in the present research.

Non-small cell lung cancer (NSCLC) is an obscure disease whose incidence is increasing worldwide day by day, and PI3Kα is one of the major targets for cell proliferation due to the mutation.     

Expedient approach for trans-esterification of β-keto esters under solvent free conditions using silica supported boric acid (SiO2–H3BO3) as a recyclable catalyst

A highly efficient trans-esterification of β-keto methyl/ethyl esters with primary, secondary, allylic, benzylic and chiral alcohols has been carried out in excellent yields under solvent-free conditions using silica supported boric acid as a heterogeneous catalyst. The surface morphology of the silica-boric acid catalyst (fresh and recycled) has been characterized by SEM and EDX techniques. This sustainable protocol resulted in a remarkable enhancement in the synthetic efficiency (87–95% yield) with high purity and eliminating the use of an environmentally toxic solvent. The work up procedure is very simple and the catalyst has been successfully recovered and recycled. The present methodology is also applicable for trans-esterification with chiral alcohols on a multi-gram scale without compromising the yield. Noteworthy features of this protocol are simple operational procedure, minimizing production of chemical waste, mild reaction conditions, easy preparation of the catalyst and its recyclability up to five cycles without any appreciable loss of catalytic activity.

A simple, mild, high yielding and minimizing chemical waste procedure for trans-esterification of β-keto methyl/ethyl esters with alcohol groups was developed under solvent-free condition using silica-boric acid as recyclable heterogeneous catalyst.     

Glycosmis arborea extract as a hepatoprotective agent

Glycosmis arborea is a plant possessing various medicinal properties. The aim of the present study was to investigate the hepatoprotective efficacy of the butanol extract obtained from the aerial parts of the plant. The test sample was prepared by extracting the material through different steps. The extract thus obtained was dissolved in normal saline. Albino rats were prophylactically treated with the extract (i.p.) for 3 weeks. At the end of 3rd week all the groups were injected with hepatotoxic agents. After 48 h of injection, blood was collected and livers were taken out. Different enzymes in the serum were assayed and histopathological study was performed with liver. Glycosmis arborea extract was able to overcome the toxic effects of hepatotoxic agents in terms of lowering the levels of serum GPT, alkaline phosphatase and increased level of SOD in serum. TBARS generation in liver was also altered. Moreover, necrosis of liver produced by carbon tetrachloride was reversed by the extract.     

Evaluation of anti-inflammatory potential of Chloranthus erectus (Buch.-Ham.) Verd. leaf extract in rats

Aim of the study

Chloranthus erectus (Buch.-Ham.) Verdcourt (Chloranthaceae) is a shrub native to tropical and temperate zone of Eastern Himalaya of India and South-East Asia and have traditionally been used as a folklore medicine to treat localised swelling, joint pain, skin inflammation, fever and bodyache. In this study, an attempt has been made to demonstrate the anti-inflammatory activity of methanol extract obtained from Chloranthus erectus leaves (MECEL) in acute, sub-acute and chronic mouse models.

Materials and methods

Inflammation in the hind paw of Wistar albino rat was induced by carrageenan, histamine and serotonin, and tissue granuloma pouch was induced by cotton pellet method. Anti-inflammatory drug—phenylbutazone was used as standard drug for comparison.

Results

In acute carrageenan-induced rat hind paw edema, oral administration of MECEL at 200 mg/kg produced significant inhibition of edema by 38.34% (p < 0.01) while the histamine- and serotonin-induced sub-acute model, the inhibition of paw edema reached 52.54% (p < 0.001) and 25.5% (p < 0.01), respectively. In a 7-day study, MECEL at 20 and 50 mg/kg produced significant suppression of cotton pellet-induced tissue granuloma formation in rats.

Conclusions

This preliminary study revealed that the methanol extract of Chloranthus erectus exhibited significant anti-inflammatory activity in the tested models, and may provide the scientific rationale for its popular folk medicine as anti-inflammatory agent.     

Drug-prescribing patterns during pregnancy in the tertiary care hospitals of Pakistan: a cross sectional study

Background

Low birth weight (LBW) is considered as a major multifaceted public health concern. Seventy-two percent of LBW infants are born in Asia. An estimation of 8% LBW infants has been reported for Eastern Mediterranean region including Iran. This study investigated contributory factors of LBW in singleton term births in Tehran, Iran. Tehran is a multicultural metropolitan area and a sample from the general population in Tehran could be regarded as a representative sample of urban population in Iran.

Methods

This was a retrospective study using data from 15 university maternity hospitals in Tehran, Iran. Data on all singleton term births in these hospitals were extracted from case records during a one calendar year. Study variables included: maternal age, maternal educational level, history of LBW deliveries, history of preterm labor, cigarette smoking during pregnancy, number of parities, chronic diseases and residential area (Tehran versus suburbs of Tehran). In order to examine the relationship between LBW and demographic and reproductive variables the adjusted logistic regression analysis was performed.

Results

In all, data for 3734 term pregnancies were extracted. The mean age of women was 25.7 (SD = 5.3) years and 5.2% of term births were LBW. In addition to association between LBW and maternal age, significant risk factors for LBW were: history of LBW deliveries [adjusted odds ratio (OR) = 2.53, 95% confidence interval (CI) = 1.06–6.03], smoking during pregnancy (OR = 4.64, 95% CI = 1.97–10.95) and chronic diseases (OR for hypertension = 3.70, 95% CI = 2.25–6.06, OR for others = 2.04, 95% CI = 1.09–3.83).

Conclusion

The findings indicate that in addition to maternal age, history of LBW deliveries; smoking during pregnancy and chronic diseases are significant determinants of LBW in this population. This is consistent with national and international findings indicating that maternal variables and risk behaviors during pregnancy play important roles on LBW.     

DRESS syndrome: a detailed insight

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious and potentially fatal adverse effect to therapeutic medications. The incidence of this condition varies among different ethnicities because of the difference in the genetic makeup. Though fever, rash and eosinophilia are essential features for the diagnosis of this syndrome, these vary from patient to patient along with the involvement of various organs such as liver, kidney, lungs, pancreas, etc. Some of the atypical features are dysphagia, agranulocytosis, and chylous ascites. Phenytoin, phenobarbitone, carbamazepine, and allopurinol are the most common drugs responsible for developing this syndrome, although the list is fairly long. Among the criteria used for the diagnosis of DRESS syndrome, European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) criteria is the most commonly used one. The management of this syndrome involves early removal of the causative agent and treatment with anti-histamines and emollients in the mild form, corticosteroids in the moderate form and plasmapheresis in the severe form along with other alternatives drugs. Healthcare professionals should be more vigilant about the early manifestations of this syndrome, as early diagnosis and treatment improve outcomes considerably.     

Simian Varicella Virus Pathogenesis in Skin during Varicella and Zoster

Primary simian varicella virus (SVV) infection and reactivation in nonhuman primates is a valuable animal model in the study of varicella zoster virus disease [varicella (chickenpox) and herpes zoster (shingles)]. To understand SVV pathogenesis in skin, we inoculated 10 rhesus macaques with SVV, resulting in varicella rash. After the establishment of latency, eight of the monkeys were immunosuppressed using tacrolimus with or without irradiation and prednisone and two monkeys were not immunosuppressed. Zoster rash developed in all immunosuppressed monkeys and in one non-immunosuppressed monkey. Five monkeys had recurrent zoster. During varicella and zoster, SVV DNA in skin scrapings ranged from 50 to 10⁷ copies/100 ng of total DNA and 2–127 copies/100 ng of total DNA, respectively. Detection of SVV DNA in blood during varicella was more frequent and abundant compared to that of zoster. During varicella and zoster, SVV antigens colocalized with neurons expressing β-III tubulin in epidermis, hair follicles, and sweat glands, suggesting axonal transport of the virus. Together, we have demonstrated that both SVV DNA and antigens can be detected in skin lesions during varicella and zoster, providing the basis for further studies on SVV skin pathogenesis, including immune responses and mechanisms of peripheral spread.     

Tribal Odisha Eye Disease Study # 11 - Particularly vulnerable tribal group eye health program. Program protocol and validation

Purpose:To describe and validate the eye health program protocol of Dongria tribal community, a particularly vulnerable tribal group (PVTG) in Rayagada district, Odisha, India.Methods:The program would consist of three segments. At people’s residences, trained community health workers (CHWs) will measure the vision and collect demographic data. In addition, vision technicians (VTs) will refract using a hand-held device and prescribe spectacles to people who improve to >6/12, N8. Others would be referred to the vision center (VC). At VC, the VT will perform a slit-lamp examination and re-refract. They would refer people with vision ≤6/12 to the secondary center (SC). At SC, referred people will receive a comprehensive eye examination and treatment. The ophthalmologist will assign the cause of blindness and visual impairment for people with visual acuity <6/12. The entire process was rehearsed in a pilot study.Results:The target population is approximately 10,000 people residing in 101 hutments on the hills of Rayagada district. The pilot study included 126 people. The mean age was 44 ± 18 years; 70% of the people were illiterate, and in this cohort, 97.6% (n = 123) had never worn spectacles. In the pilot study, 41% of the people had cataract, and 12% had pterygium. The agreements between optometrist versus VTs and between optometrist versus CHWs were good (k = ~0.8–1.0) in all eye conditions except for strabismus (k = ~0.56–0.65)Conclusion:The pilot study confirms the program modality, and when completed, it would help in the planning and resource allocation of Odisha PVTG eye care.