Search

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were −7.7, −6.3 and −5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the fifth leading cause of mortality and the most lethal gynecologic malignancy among females. It may arise from atypical borderline tumors (Type I) or serous tubal intraepithelial carcinoma (Type II). The diagnosis of cancer at its early stages is difficult because of non-specific symptoms, most patients are diagnosed at the advanced stage. Several drugs and therapeutic strategies are available to treat ovarian cancer such as surgery, chemotherapy, neoadjuvant therapy, and maintenance therapy. However, the cancer cells have developed resistance to a number of available therapies causing treatment failure. This emerging chemoresistance in ovarian cancer cells is becoming an obstacle due to alterations in multiple cellular processes. These processes involve altered drug target response, drug pumps, detoxification systems, lower sensitivity to apoptosis, and altered proliferation, and are responsible for developing resistance to anticancer medicines. Various research reports have evidenced that these altered processes might play a role in the emergence of resistance. This review addresses the recent advances in understanding the underlying mechanisms of ovarian cancer resistance and covers sophisticated alternative pathways to overcome these resistance mechanisms in patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Yellow fever is a flavivirus having plus-sensed RNA which encodes a single polyprotein. Host proteases cut this polyprotein into seven nonstructural proteins including a vital NS3 protein. The present study aims to identify the most effective inhibitor against the helicase (NS3) using different advanced ligand and structure-based computational studies. A set of 300 ligands was selected against helicase by chemical structural similarity model, which are similar to S -adenosyl-l-cysteine using infiniSee. This tool screens billions of compounds through a similarity search from in-built chemical spaces (CHEMriya, Galaxi, KnowledgeSpace and REALSpace). The pharmacophore was designed from ligands in the library that showed same features. According to the sequence of ligands, six compounds ( 29 , 87 , 99 , 116 , 148 , and 208 ) were taken for pharmacophore designing against helicase protein. Subsequently, compounds from the library which showed the best pharmacophore shared-features were docked using FlexX functionality of SeeSAR and their optibrium properties were analyzed. Afterward, their ADME was improved by replacing the unfavorable fragments, which resulted in the generation of new compounds. The selected best compounds ( 301 , 302 , 303 and 304 ) were docked using SeeSAR and their pharmacokinetics and toxicological properties were evaluated using SwissADME. The optimal inhibitor for yellow fever helicase was 2-amino- N -(4-(dimethylamino)thiazol-2-yl)-4-methyloxazole-5-carboxamide ( 302 ), which exhibits promising potential for drug development.Communicated by Ramaswamy H. Sarma.

This research has been designed to analyze the risk factors of major eye diseases and the genetic alterations contributing to the manifestation of such disease. For this purpose, data was collected from 256 patients diagnosed by an ophthalmologist by using a specialized questionnaire. Blood samples were collected from 100 patients to perform a genetic investigation of cataracts. Whole genomic DNA was extracted from blood samples via the phenol-chloroform method. The purified DNA was used as the template for the amplification of about 400 bp fragments amplifying exons 1 and 2 of the CRYAA gene. The statistical analysis showed that 68% of individuals were blind due to cataracts. During molecular analysis, nucleotide sequences obtained have resulted in one silent mutation that occured at 20 positions in exon 2. It was replacing A>G which in turn substitutes the Lysine at position 70 for Arginine. It was interpreted by statistical analysis that this mutation did not result in a significant change in the CRYAA gene. In addition, protein analysis showed no significant changes in the structure of normal and mutated genes. At last, it is concluded that environmental risk factors play a major role in the studied diseases as compared to genetic factors. It is recommended to extend the study to a larger population to study all exons of the CRYAA gene as well as develop better estimates of the magnitude of the problems of visual loss and eye diseases in the Pakistani population.

Polycystic ovary syndrome (PCOS) is a highly widespread disorder caused by a disturbed endocrine system. The Rotterdam criteria have classified 4 phenotypes of PCOS. This syndrome has multifactorial pathophysiology triggered by a disturbed neuroendocrine system, which further produces abnormal levels of luteinizing hormone, follicle-stimulating hormone, androgen, estrogen, and progesterone, leading towards the risk of metabolic and reproductive diseases. PCOS is associated with an increased risk of developing health problems like hyperinsulinemia, diabetes mellitus, hypertension, cardiovascular disorders, dyslipidaemia, endometrial hyperplasia, anxiety and depression. These days, PCOS has become a scientific issue due to complex aetiology with multi- complex physiology. Due to the unavailability of specific medicines, there is no cure for PCOS; however, certain symptoms could be treated. The scientific community is actively looking for various treatment options too. In this context, the current review summarizes the challenges, consequences and various treatment options for PCOS. Various literature reports provide evidence that PCOS can be identified in early infancy, adolescents and women at the menopausal stage. Most commonly, PCOS is caused by multifactorial agents, including genetics and negative lifestyle. Metabolic consequences from obesity, insulin resistance, and vascular disorder have increased the rate of PCOS. This study also highlights psychological morbidity in PCOS women that have an adverse effect on health-related quality of life (HRQoL). PCOS symptoms can be treated using different strategies, including oral contraceptive drugs, surgical treatment (laparoscopic ovarian drilling (LOD), assisted reproductive techniques (ART), and Chinese acupuncture treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)