A Computational Study of Phenothiazine Derivatives as Acetylcholinesterase Inhibitors Targeting Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors act as anti-Alzheimer's agents. Phenothiazine derivatives are considered momentous anti-Alzheimer's agents because of their AChE inhibitory activity. The elevated levels and increased expression of this protein have been associated with Alzheimer's disease. Coumarin-fused phenothiazines have emerged as significant anti-Alzheimer's agents due to their notable receptor inhibitory activity. OBJECTIVE: Some unique phenothiazine analogs were designed, and computational studies were conducted to explore their inhibitory activity against the AChE enzyme (PDB id: 4EY7) by using the Schrodinger suite-2019-4. METHODS: Docking studies were conducted by using the Glide module; binding free energies were calculated by means of the Prime MM-GBSA module, and Molecular dynamics (MD) simulation was performed by using the Desmond module of the Schrodinger suite. Glide scores were used to find out the binding affinity of the ligands with the target 4EY7. RESULTS: The compounds exhibited enhanced hydrophobic interactions and formed hydrogen bonds, effectively impeding Acetylcholinesterase. The Glide scores for the compounds ranged from -13.4237 to -8.43439, surpassing the standard (Donepezil) with a score of -16.9898. Interestingly, a positive value was obtained for the MM-GBSA binding of the potent inhibitor. To gain insights into the dynamic behavior of the protein A8, molecular dynamics (MD) simulations were employed. CONCLUSION: Based on the results, the study concludes that phenothiazine derivatives show promise as acetylcholinesterase inhibitors. Compounds with notable Glide scores are poised to exhibit significant anti-Alzheimer's activity, suggesting their potential therapeutic efficacy. Further in vitro and in vivo investigations are warranted to validate and explore the therapeutic potentials of these compounds.

In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as 5HT6R Antagonists Targeting Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a type of dementia that affects neuronal function, leading to a decline in cognitive functions. Serotonin-6 (5HT6) receptors are implicated in the etiology of neurological diseases. 5HT6 receptor antagonists act as anti-dementia agents. PDB ID: 7YS6 represents a membrane protein, and amplification and overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin- 6 receptor. OBJECTIVES: Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50] were designed using in-silico methods to evaluate their 5HT6 receptor antagonistic activity. Molecular modeling techniques were employed to study the ligands [A2 to A50] in interaction with the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4. METHODS: Molecular modeling studies of the designed ligands [A2 to A50] were conducted using the Glide module. In-silico ADMET screening was performed using the QikProp module, and binding free energy calculations were carried out using the Prime MM-GBSA module within the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards 5HT6 receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a 100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1, which is based in New York, NY. RESULTS: The majority of the designed ligands exhibited strong hydrogen bonding interactions and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these ligands fell within the recommended values for drug-likeness. It is worth noting that the MM-GBSA binding free energy of the most potent inhibitor was positive, indicating a strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand (A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation. CONCLUSION: The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential.

QSAR, molecular docking, molecular dynamics and MM-GBSA approach for identification of prospective benzotriazole-based SARS-CoV 3CL protease inhibitors.

The 3CL Protease of severe acute respiratory syndrome coronavirus (SARS-CoV), responsible for viral replication, has emerged as an essential target for designing anti-coronaviral inhibitors in drug discovery. In recent years, small molecule and peptidomimetic inhibitors have been used to target the inhibition of SARS-CoV 3CL Protease. In this study, we have developed 2D and 3D Quantitative structure activity relationship (QSAR) models on 3CL protease inhibitors with good predictive capability to propose inhibitors with improved affinities. Based on the 3 D contour maps, three new inhibitors were designed in silico, which were further subjected to molecular docking to explore their binding modes. The newly designed compounds showed improved interaction energies toward SARS-CoV-3CLPro due to additional interactions with the active site residues. The molecular docking studies of the most potent compounds revealed specific interactions with Glu 166 and Cys 145. Furthermore, absorption, distribution, metabolism, elimination (ADME) and drug-likeness evaluation revealed improved pharmacokinetic properties for these compounds. The molecular dynamics simulations confirmed the stability of the interactions identified by docking. The results presented would guide the development of new 3CL protease inhibitors with improved affinities in the future.Communicated by Ramaswamy H. Sarma.

Do parents talk to their adolescent children about sex?--findings from a community survey in Singapore

<p><b>INTRODUCTION</b>Sexually transmitted infections have increased sharply among adolescents both locally and internationally in recent years. Parents play an important role in their children's sexual health development. An integral part of this includes effective parent-child sexuality communication.</p><p><b>MATERIALS AND METHODS</b>A nationwide cross-sectional community-based household survey was conducted in Singapore between August 2008 and March 2009 to assess parents'/caregivers' attitudes and practices regarding caregiver-child sexuality communication. With an overall response rate of 81.4%, 1169 questionnaires from parents/caregivers of children aged 10 to 17 years were analysed.</p><p><b>RESULTS</b>Almost all (94.2%) the caregivers were parents. A majority (>80%) of caregivers considered talking to their children about sexuality issues such as abstinence, consequences of premarital sex and condom use as important. However, a significantly lower percentage (about 60%) felt comfortable and confident doing so. Only 8.3% among them discussed sexual health issues with their children very often, 37.2% sometimes, 22.0% seldom/hardly ever (once or twice) and 32.5% never, in the past year. In the multivariate analysis, caregiver-child sexuality communication was significantly associated with caregivers' relationship to children, ethnicity, educational level, and their perceived levels of comfort and confidence in sexuality communication.</p><p><b>CONCLUSION</b>Caregivers generally felt it was important but were significantly much less comfortable and confident talking about sexuality issues with their children, which leads to a lower frequency of caregiver-child sexuality communication. Educational programmes on adolescent sexual health targeting parents/caregivers are needed. They must be equipped with skills and provided with resources to enable them to talk to their adolescent children about sexuality.</p>