Muhammad Shah

الملخص أهداف البحث أدى التهديد العالمي المتزايد للعدوى الفيروسية المنتقلة من الحيوان إلى الإنسان إلى زيادة الاهتمام بالممرضات الناشئة مثل فيروس جدري القرود. هدفت هذه الدراسة إلى استكشاف إمكانية إعادة توظيف الأدوية بوصفها استراتيجية علاجية فعّالة ضد فيروس جدري القرود، مع التركيز على الارتباط الجيني الوثيق لهذا الفيروس بفيروسي الوقس والجدري. طرق البحث نظراً للتشابه البنيوي والتطوري بين فيروسات جنس الأورثوبوكس، تم اختيار دواء تيكوفيريمات، وهو دواء معتمد من هيئة الغذاء والدواء الأمريكية لعلاج الجدري، كدواء مرجعي. استُخدم نهج وصفي تحليلي لتقييم طاقات الارتباط لـ 38 دواءً معتمداً من هيئة الغذاء والدواء الأمريكية من أربع فئات علاجية. كما أُجري الالتحام الجزيئي ضد بروتينات مستهدفة رئيسية من جنس الأورثوبوكس، تلاه إجراء محاكاة الديناميكيات الجزيئية للتحقق من ثبات وتفاعلات أفضل معقدات الدواء والبروتين. النتائج أظهرت عدة مركبات ألفة ارتباط أقوى من الدواء المرجعي تيكوفيريمات، مما يشير إلى إمكانية إعادة توظيفها كعوامل مضادة لفيروس جدري القرود. وقد تضمنت المركبات الواعدة دارونافير، وسيميبريفير، وتيبرانافير، وإندينافير، وساكوينافير، وباريتابريفير، وإيداروبيسين، وغليكابريفير، حيث أظهرت درجات التحام جزيئي متفوقة مقارنة بالدواء المرجعي. كما دعمت محاكاة الديناميكيات الجزيئية ثبات هذه المعقدات الدوائية البروتينية واستمرار تفاعلاتها داخل المواقع النشطة للبروتينات المستهدفة، بما في ذلك الروابط الهيدروجينية والسلوك الديناميكي الملائم. الاستنتاج تقدم هذه الدراسة دلائل واعدة على إمكانية إعادة توظيف بعض الأدوية المعتمدة كمرشحات علاجية محتملة ضد فيروس جدري القرود. كما تدعم نتائج الالتحام الجزيئي ومحاكاة الديناميكيات الجزيئية جدوى هذه المركبات وثباتها، مما يعزز إمكانية تطوير تطبيقات علاجية جديدة قد تسهم في تحسين الاستجابة الصحية العامة وزيادة القيمة العلاجية والتجارية للأدوية المعاد توظيفها. ومع ذلك، تبقى الحاجة قائمة إلى دراسات تجريبية وسريرية إضافية للتحقق من فعاليتها وسلامتها ضد فيروس جدري القرود.

Bond dissociation energy prediction for the carbon halogen (C–X) bond is quite important in chemistry, due to range applications of C–X bond in the drug design, reaction mechanism and material sciences fields. In the present research, a robust machine learning workflow was explored, to accurately predict the bond dissociation energy values of C–X bond. For the systematic identification of the optimized LightGBM Regressor as the top performing model, the automated machine leaning (Automl) framework, the Tree Based Pipeline Optimization Tool (TPOT) was employed. Additionally, tenfold cross-validation was used to rigorously confirm the model’s robustness. The final model exhibited outstanding predictive capability, with a coefficient of determination (R 2 ) of 0.93 on the internal test set, and 0.95 on a more stringent external validation set. Moreover, interpretation of the model via SHapley Additive exPlanations (SHAP) suggests that the model predictions are based on chemically intuitive concepts, including electronegativity difference, halogen atomic number, and local atomic charges. This work thus provides a tool for bond dissociation energy prediction that is both highly accurate and interpretable, while simultaneously demonstrating a powerful contemporary workflow for producing machine learning models that are interpretable for basic problems in chemistry.

Aim Cobra venom phospholipase A2 (PLA2) has been known to induce life threatening effects post-envenomation in the victims. Being the most abundant and noxious component of snake venom, present study was envisaged to investigate new drug candidates against PLA2 enzyme.Methods Amide and sulfonamide thiazole derivatives were synthesized and characterized using FTIR, 1HNMR and 13CNMR followed by docking targeted protein techniques. Furthermore, synthetic analogues were evaluated in vitro for their potentials to neutralize PLA2 activity.Results Among the pool of synthetic derivatives, compound (7) (ethyl 2-(2-(4-isobutylphenyl)propanamido)thiazole-4-carboxylate) was found to be completely effective (p > 0.05; IC50 = 1 nM) to mask cent percent PLA2 activity. Moreover, Ramachandran plot further conferred about the location of amino acid residues in the most favored region and, therefore, attributed to confiscate PLA2 activity. Furthermore, ADME profile suggested that compound (7) possesses systemic bioavailability and efficacy with favorable safety profile (high solubility, membrane permeability, metabolic stability, and low potential for off-target results).Conclusion Present study highlighted compound (7) as a potential PLA2 inhibitor to reverse PLA2-induced snake venom poisoning in future.

values were assessed, confirming acceptable cytotoxicity profiles for potent compounds. Molecular dynamic simulation substantiated the binding mechanism revealing that compound 12l maintains robust stability with the target protein. Furthermore, compounds predicted to have minimal oral toxicity and high intestinal absorption make them promising candidates for drug development. These findings paved the way for the potent clinical application of these dihydropyrimidine-2-thiones as efficient SARS-CoV-2 therapeutics.

Fernandoa adenophylla, due to the presence of phytochemicals, has various beneficial properties and is used in folk medicine to treat many conditions. This study aimed to isolate indanone derivative from F. adenophylla root heartwood and assess in-vitro anti-inflammatory and anti-diabetic characteristics at varying concentrations. Heat-induced hemolysis and glucose uptake by yeast cells assays were conducted to evaluate these properties. Besides, docking analyses were performed on four molecular targets. These studies were combined with molecular dynamics simulations to elucidate the time-evolving inhibitory effect of selected inhibitors within the active pockets of the target proteins (COX-1 and COX-2). Indanone derivative (10-100 µM) inhibited the lysis of human red blood cells from 9.12 ± 0.75 to 72.82 ± 4.36% and, at 5-100 µM concentrations, it significantly increased the yeast cells' glucose uptake (5.16 ± 1.28% to 76.59 ± 1.62%). Concluding, the isolated indanone might act as an anti-diabetic agent by interacting with critical amino acid residues of 5' adenosine monophosphate-activated protein kinase (AMPK), and it showed a binding affinity with anti-inflammatory targets COX-1, COX-2, and TNF-α. Besides, the obtained results may help to consider the indanone derivative isolated from F. adenophylla as a promising candidate for drug delivery, subject to outcomes of further in vivo and clinical studies.

BACKGROUND: This work aims to explore the anticancer potential of compounds isolated from Heterophragma adenophyllum (H. adenophyllum) leaves and investigate their molecular interactions with cancer-related targets. H. adenophyllum, a plant with potential medicinal properties, offers a promising avenue for such investigations.METHODS: The study involved the extraction and isolation of compounds from H. adenophyllum leaves, followed by an evaluation of their cytotoxicity against U87 malignant glioma cell lines. U87 malignant glioma cell lines were exposed to different concentrations of the compounds for cytotoxicity. The inhibitory effect on cell growth was analyzed, and IC50 values were determined. Additionally, molecular docking studies were conducted to investigate the interactions of the compounds with two important cancer-related targets, the X-ray crystal structure of duplex DNA and epidermal growth factor receptor (EGFR).RESULTS: The cytotoxicity evaluation demonstrated dose-dependent inhibition of cell growth by the isolated compounds. Peshawaraquinone (pesh-quinone) exhibited the highest cytotoxicity, with an IC50 value of 87.9 μM. The indanone derivatives (Ind), lapachol (Lappa), and α-lapachone (Alpha Lappa) showed IC50 values of 174.9 μM, 141.4 μM, and 132.8 μM, respectively. In the molecular docking studies, the compounds displayed significant interactions with key residues within the active sites of the duplex DNA and EGFR proteins, suggesting potential binding affinity and therapeutic relevance.CONCLUSIONS: Results of this work shoes that compounds isolated from H. adenophyllum leaves possess significant anticancer potential. The observed cytotoxic effects against U87 malignant glioma cells and the molecular interactions with cancer-related targets further support the promise of these compounds as potential anticancer agents.

Abstract In the search for potent bioactive compounds, a series of tetrahydro-2 H -1,3,5-thiadiazine-2-thiones ( 1 – 13 ) were synthesized in good yield and characterized by means of 1 H NMR, 13 C NMR, and mass spectral data. The anticancer activity of the compounds was evaluated against HeLa cell line and anti-inflammatory potential via nitric oxide (NO) inhibition. Among the screened compounds, 2-(5-(3-methoxypropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid ( 3 ), 2-(5-cyclopropyl-6-thioxo-1,3,5-thiadiazinan-3-yl) propionic acid ( 5 ), 2-(5-cyclopropyl)-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid ( 6 ), and 2-(5-butyl-6-thioxo-1,3,5-thiadiazinan-3-yl) acetic acid ( 9 ) were the most potent against HeLa cell line with IC 50 values <4 µM, whereas the rest of the series exhibited moderate-to-good activities. All the compounds were potent NO inhibitors with IC 50 values ranging from <0.4 to 14.9 µM. Docking studies, binding orientations, and interaction plots showed strong interaction of the studied compounds with the inducible NO synthase enzyme via strong hydrogen bonds and hydrophobic interactions, which authenticate the in vitro results. These newly synthesized compounds could lead to the discovery of anticancer drugs.

Diabetes mellitus (DM) is a metabolic disorder majorly arising from the pathophysiology of the pancreas manifested as a decline in the insulin production or the tissue’s resistance to the insulin. In this research, we have rationally designed and synthesized new succinimide–thiazolidinedione hybrids for the management of DM. In a multistep reaction, we were able to synthesize five new derivatives (10a–e). All the compounds were new containing a different substitution pattern on the N-atom of the succinimide ring. Initially, all the compounds were tested against the in vitro α-glucosidase, α-amylase, PTP1B, and DPP4 targets. In all of these targets, the compound 10d was observed to be the most potential antidiabetic agent. Based on this, the antidiabetic activity of the compound 10d was further investigated in experimental animals, which overall gave us encouraging results. The molecular docking studies of the compound 10d was also performed against the target enzymes α-glucosidase, α-amylase, PTP1B, and DPP4 using MOE. Overall, we observed that we have explored a new class of compounds as potential antidiabetic agents.

Aim: The deaths of thousands of people and millions affected by diabetes mellitus triggered us to look for alternative possible solutions to cure diabetes and its complications. Materials & methods: A series of hydrazinylthiazole carboxylates (3a–n) was prepared by cyclocondensation reaction of thiosemicarbazones with ethyl 2-chloroacetoacetate. These compounds were screened for antidiabetic potential through α-amylase inhibition, antiglycation and antioxidant assays. Results & conclusion: Most of the compounds exhibited a promising antidiabetic property. Compounds 3e and 3h showed excellent α-amylase and glycation inhibition properties. The hemolytic assay indicated that all compounds are biocompatible. Docking studies carried out on α-amylase target showed correlation between in vitro inhibition and binding energy.