Investigation of 3-Phenylcoumarin Derivatives as Potential Multi-target Inhibitors for Human Cholinesterases and Monoamine oxidases: A Computational Approach.

Alzheimer's disease (AD) is the predominant etiology of dementia, impacting a global population of approximately 50 million individuals. In the field of medicinal chemistry, there have been notable advancements in the utilization of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors for the purpose of addressing the neurotransmitter shortage associated with Alzheimer's disease (AD). A selection of previously synthesized 3-Phenylcoumarin derivatives (5a-m) were selected for examination in the pursuit of potential multi-targeting inhibitors of MAO-A, MAO-B, AChE, and BChE. The stability and reactivity of the compounds were investigated through the utilization of density functional theory (DFT) simulations. Subsequently, a CoMFA technique, grounded in 3D-QSAR principles, was employed to construct a model and predict the inhibitory properties of analogues belonging to the class of 3-phenylcoumarin derivatives. Through the application of molecular docking methodologies, we have employed predictive analyses to determine the potential binding interactions and stability of the drugs under investigation. The results obtained from the present investigation indicate that the 3-phenylcoumarin derivatives possess a reactive electronic characteristic that is crucial for their anti-cholinesterase activity. Compound 5a demonstrated a noteworthy binding score with AChE, BChE, MAO-A and MAO-B, respectively, indicating a robust binding affinity.

Computational Exploration of Fluorocyclopentenyl-purines and-pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer.

The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3 kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4 kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using in vitro and in vivo approaches.

Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (5a-5j) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals. All of the investigated compounds displayed a more powerful inhibitory profile than the reference agent, KH2PO4 particularly compound 5h and 5a exhibited strong inhibitory potential against ALP with IC50 value of 0.365 ± 0.011 and 0.436 ± 0.057 µM respectively. In addition, Lineweaver-Burk plots revealed the non-competitive inhibition mode of the most powerful derivative i.e., 5h (ki value 0.5 µM). To investigate the putative binding mode of selective inhibitor interactions, molecular docking was performed. It is recommended that future research will focus on developing selective alkaline phosphatase inhibitors by modifying the structure of the 5h derivative.

Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer.

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of -41.48 and -29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of -37.92 and -38.5 kJ/mol against ERBB and -41.2 and -46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.

4-Phthalimidobenzenesulfonamide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: DFTs, 3D-QSAR, ADMET, and Molecular Dynamics Simulation.

INTRODUCTION: Alzheimer's disease is a form of dementia which affects majority of the people. It is characterized by memory loss and other cognitive function disabilities and is one of the most challenging neurodegenerative disorders to treat because of its progressive nature. The disease affects millions of people all around the world, and the number of those affected is expanding every day. In the previous study, the 4-phthalimidobenzenesulfonamide derivatives were synthesized as AChE and BChE inhibitors, and here, we were aiming to further reporting in silico studies of these compounds for efficient drug discovery process and to find out the potential lead compounds. METHODS: In silico characterization included density functional theory (DFT) studies, 3D-QSAR, ADMET properties, molecular docking, and molecular dynamic simulations. The geometries of all derivatives were optimized using B3LYP method and 6-311G basis set. RESULTS: The findings of the current study revealed that 4-phthalimidobenzenesulfonamide derivatives exhibited a reactive electronic property which is essential for anticholinesterase activity. Moreover, optimized structures were subjected to molecular docking studies with targeted protein. The compounds 2c and 2g showed excellent binding score of -37.44 and -33.67 kJ/mol with BChE and AChE, respectively, and exhibited strong binding affinity. The potent derivatives produced stable complex with amino acid residues of active pocket of both BChE and AChE. The stability of protein-ligand complexes was determined by molecular dynamic simulation studies, and results were found in correlation with molecular docking findings. CONCLUSION: Findings of the current study suggested that these derivatives are potent inhibitors of cholinesterase enzyme.

Self and Peer Assessment of Teachers' Attitude towards Teaching.

OBJECTIVE: To appraise the attitude of the teachers towards teaching and the factors affecting their attitudes, and compare self-assessed attitudes of the medical teachers with teachers in social sciences. STUDY DESIGN: Cross-sectional descriptive study. PLACE AND DURATION OF STUDY: Wah Medical College (WMC), Wah Cantt, from January to August 2016. METHODOLOGY: Teachers were categorized as having positive, average, and below average attitudes on the basis of a close-ended questionnaire comprising of 32 items. All the items were ranked on 5 points Likert-scale. Questionnaires were filled by the teachers twice, first for themselves and then for their peers. RESULTS: There were 91 self-assessments [53 medical teachers (MT) and 38 social sciences teachers (SST)], and 59 peer assessments (31 MT and 28 SST). Overall, the attitude of teachers was average as 99 teachers (66%) fell in this category. Out of 53 MT, 9 (17%) had a positive attitude and 43 (81.1%) had average attitude. Out of 38 SST, 5 (13.2%) had positive attitude and 21 (55.3%) had average attitude. MT self-accounted attitude was significantly higher than the SST (x²=15.975, p=<0.001) in comparison to peer assessed attitude, which was equal in the two groups (x²=2.778, p=0.249). Variables significantly associated with good attitude, were female gender, junior designation and more experienced. CONCLUSION: Overall teachers attitude was average in both faculties. But the self-accounted attitude was higher among MT than SST. Teachers who are junior in qualification and designation, females, medical by profession, and more experienced need to improve their self-assessment and reflection skills.