Rational drug repurposing for alzheimer's treatment using in-silico ligand and structure-based approaches

Abstract Alzheimer's disease is a devastating neurodegenerative disorder characterized by memory loss and cognitive decline. New AD treatments are essential, and drug repositioning is a promising approach. In this study, we combined ligand-based and structure-based approaches to identify potential candidates among FDA-approved drugs for AD treatment. We used the human acetylcholinesterase receptor structure (PDB ID: 4EY7) and applied Rapid Overlay of Chemical Structures and Swiss Similarity for ligand-based screening.Computational shape-based screening revealed 20 out of 760 FDA approved drugs with promising structural similarity to Donepezil, an AD treatment AChE inhibitor and query molecule. The screened hits were further analyzed using docking analysis with Autodock Vina and Schrodinger glide. Predicted binding affinities of hits to AChE receptor guided prioritization of potential drug candidates. Doxazosin, Oxypertine, Cyclopenthiazide, Mestranol, and Terazosin exhibited favorable properties in shape similarity, docking energy, and molecular dynamics stability.Molecular dynamics simulations confirmed the stability of the complexes over 100 ns. Binding free energy analysis using MM-GBSA indicated favourable binding energies for the selected drugs. ADME, formulation studies offered insights into therapeutic applications and predicted toxicity.This comprehensive computational approach identified potential FDA-approved drugs (especially Doxazosin) as candidates for repurposing in AD treatment, warranting further investigation and clinical assessment.

Safety and Protective Effects of Influenza Vaccination in Pregnant Women on Pregnancy and Birth Outcomes in Pune, India: A Cross-Sectional Study.

BACKGROUND: Maternal influenza vaccination provides effective protection against influenza infections in pregnant women and their newborns. In India, the influenza vaccine has not yet been offered through immunization programs, owing to the lack of sufficient safety data for pregnant Indian women. METHODS: This cross-sectional observational study enrolled 558 women admitted to the obstetrics ward of a civic hospital in Pune. Study-related information was obtained from the participants through hospital records and interviews using structured questionnaires. Univariate and multivariable analysis was used, and the chi-square test with adjusted odds ratio was estimated to account for vaccine exposure and the temporal nature of each outcome, respectively. RESULTS: Women not vaccinated against influenza during pregnancy had a higher risk of delivering very LBW infants, and possible protective effects were suggested (AOR 2.29, 95% CI 1.03 to 5.58, p = 0.03). No association was observed between maternal influenza vaccination for Caesarean section (LSCS) (AOR 0.97, 95% CI, 0.78, 1.85), stillbirth (AOR 1.8, 95% CI 0.18, 24.64) and NICU admission (AOR, 0.87, 0.29 to 2.85), and congenital anomaly (AOR, 0.81, 0.10 to 3.87). INTERPRETATION: These results show that the influenza vaccine administered during pregnancy is safe and might lower the risk of negative birth outcomes.

A Current Perspective on the Potential of Nanomedicine for Anti-Tuberculosis Therapy.

Tuberculosis (TB) is one of the ten infectious diseases that cause the highest amount of human mortality and morbidity. This infection, which is caused by a single pathogen, Mycobacterium tuberculosis, kills over a million people every year. There is an emerging problem of antimicrobial resistance in TB that needs urgent treatment and management. Tuberculosis treatment is complicated by its complex drug regimen, its lengthy duration and the serious side-effects caused by the drugs required. There are a number of critical issues around drug delivery and subsequent intracellular bacterial clearance. Drugs have a short lifespan in systemic circulation, which limits their activity. Nanomedicine in TB is an emerging research area which offers the potential of effective drug delivery using nanoparticles and a reduction in drug doses and side-effects to improve patient compliance with the treatment and enhance their recovery. Here, we provide a minireview of anti-TB treatment, research progress on nanomedicine and the prospects for future applications in developing innovative therapies.

A novel approach to develop an animal model for oral submucous fibrosis.

Epidemiological data have proved the association of consumption of areca nut with the causation of oral submucous fibrosis (OSF). OSF is a chronic inflammatory disease with the potential for malignant transformation from 7 to 13%. The establishment of animal models makes it easier for researchers to focus on the therapeutic options to combat this disease further. We developed and compared two areca nut extract (ANE) administration methods in Swiss albino mice to establish OSF. This study compared an invasive intrabuccal injection technique with a non-invasive intraoral droplet administration. The duration of induction was around 12 weeks. Histopathology (H&E, Masson's trichrome staining) and gene expression analysis (COL-I, COL-II, and α-SMA) were performed using RT-PCR to confirm the OSF in animals. Our study showed that ANE administration through the intraoral droplet method exhibited significantly higher fibrosis than the intrabuccal injections, as evidenced by the H&E and Masson's trichrome staining. Furthermore, intraoral administration of ANE significantly upregulated the mRNA expression of COL-I, COL-II, and α-SMA, as revealed by the RT-PCR analysis. The non-invasive droplet method could simulate the absorption of areca nut seen in humans through daily dosing. This study establishes the intraoral droplet method as an efficient and non-invasive method to administer the ANE to develop OSF. These findings will aid in the efficient development of OSF animal models for interventional studies, including screening novel drugs in the reversal of the OSF.

Antidiabetics Interactions with Herbs: A Compressive Review.

Diabetes mellitus is a chronic illness with a variety of causes and pathophysiology. For the management of diabetes, various synthetic antidiabetic drugs are available. Still, people prefer complementary and alternative therapies as well as traditional herbal home remedies because they are perceived to be free of side effects and generally recognized as safe due to their natural origin. Hence, worldwide, the majority of the population is consuming herbs and/or herbal products in their daily routine. It has been observed that individuals with diabetes also consume herbs/herbal products either with or without medical supervision. This co-consumption of antidiabetic medications and herb/herbal products may result in herb-drug interactions, which might be potentially beneficial or harmful or, in some cases, even fatal. Most of the times, these interactions remain unnoticed or undiagnosed due to lack of knowledge and awareness about them. In this review, the authors have summarized some important aspects related to the herb-drug interaction (HDI), which include methods for prediction and mechanism of HDI (pharmacokinetic and pharmacodynamic) and also the clinical and experimental literature on herb-drug interactions (HDI) in the treatment of diabetes. Authors have attempted to categorize the interactions between oral hypoglycemic agents and various herbs as beneficial or harmful based on the results reported in the original research work.

Novel Targets for Antimicrobials.

Antimicrobial resistance (AMR) is the phenomenon developed by microorganism on exposure to antimicrobial agents, making them unresponsive. Development of microbial confrontation is a severe rising risk to global community well-being as treatment in addition, management of such resistant microbial infections is difficult and challenging. The situation requires action across all government sectors and society. The change in the molecular target on which antimicrobial drugs act is one of the key mechanisms behind AMR. One of the approaches to battle with AMR can be exploring newer molecular targets in microbes and discovering new molecules accordingly. There are various examples of novel targets such as biomolecules involving in biosynthesis of cell wall, biosynthesis of aromatic amino acid, cell disunion, biosynthesis of fatty acid, and isoprenoid biosynthesis and tRNA synthetases. Fatty acid biosynthesis (FAB) and their enzymes among all the above is the more appealing target for the advancement of new antimicrobial agents. Number of promising inhibitors have been developed for bacterial fatty acid synthesis (FAS) and also few of them are clinically used. Some of these potential inhibitors are found to be used in development of new antibacterial as a lead compound and have been discovered from high throughput screening processes like Platencimycin and their analogue, Platencin. The review majorly encompasses bacterial FAB in type II FAS system and potential inhibitors with respective targets of novel antibacterial.