PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras.

In the realm of oncology, the transformative impact of PROTAC (PROteolysis TAget-ing Chimeras) technology has been particularly pronounced since its introduction in the 21st cen-tury. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest in addressing a diverse array of medical conditions. This ex-panded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders. This comprehensive review explores the broadening landscape of PROTAC application, high-lighting ongoing developments and innovations aimed at deploying these molecules across a spectrum of diseases. Careful consideration of the design challenges associated with PROTACs reveals that, when appropriately addressed, these compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives. To evaluate the efficacy of PROTAC molecules, a diverse array of assays is employed, ranging from High-Throughput Imaging (HTI) assays to Cell Painting assays, CRBN engagement assays, Fluorescence Polarization assays, amplified luminescent proximity homogeneous assays, Time-resolved fluorescence energy transfer assays, and Isothermal Titration Calorimetry assays. These assessments collectively contribute to a nuanced understanding of PROTAC performance. Looking ahead, the trajectory of PROTAC technology suggests its potential recognition as a ver-satile therapeutic strategy for an expansive range of medical conditions. Ongoing progress in this field sets the stage for PROTACs to emerge as valuable tools in the multifaceted landscape of medical treatments.

Formulation, characterization and in-vivo evaluation of standardized Tabernaemontana divericata extract hydrogel for wound healing.

BACKGROUND: Tabernaemontana divaricata (TD) from the Apocynaceae family exhibits traditional therapeutic properties such as anti-inflammatory, antioxidant, and acetylcholinesterase activity, etc. OBJECTIVE: To formulate and evaluate the wound healing potential of standardized ethanolic extract of TD leaves hydrogel on experimental models of wounds in Wistar rats with the design of experiment approach. METHODS: The prepared PVA-based hydrogel of TD extract was evaluated. In-vivo, wound healing activities using excision, incision, and burn wound models were performed concerning percent wound contraction, epithelialization period, tensile strength, and histological analysis. RESULTS: On the 20th day of the excision model, percentage wound contraction for 0.5 mg/ml and 1 mg/ml extract hydrogel was found to be 90.35 % ± 0.46 and 97.28 % ± 0.59, respectively, while on the 9th day of incision model, the tensile strength of both doses of hydrogel was found to be 191.16 ± 1.51 g and 201.00 ± 1.29 g, respectively, indicating that both concentrations of the hydrogel showed significant (P < 0.05) wound healing as compared to disease control and vehicle control group. The histopathological study of hydrogel showed no necrotic cells and a greater amount of collagen. Furthermore, in the burn wound model, both doses of TD hydrogel had significant wound-healing activity, as demonstrated by a reduction in the time needed for epithelialization and an increase in the rate of wound contraction (P < 0.05). CONCLUSION: The proposed formulation showed potential for wound healing and may be studied further in clinical trials.

Current biomarkers and treatment strategies in Alzheimer disease: An overview and future perspectives.

Alzheimer's disease (AD), a progressive degenerative disorder first identified by Alois Alzheimer in 1907, poses a significant public health challenge. Despite its prevalence and impact, there is currently no definitive ante mortem diagnosis for AD pathogenesis. By 2050, the United States may face a staggering 13.8 million AD patients. This review provides a concise summary of current AD biomarkers, available treatments, and potential future therapeutic approaches. The review begins by outlining existing drug targets and mechanisms in AD, along with a discussion of current treatment options. We explore various approaches targeting Amyloid ß (Aß), Tau Protein aggregation, Tau Kinases, Glycogen Synthase kinase-3ß, CDK-5 inhibitors, Heat Shock Proteins (HSP), oxidative stress, inflammation, metals, Apolipoprotein E (ApoE) modulators, and Notch signaling. Additionally, we examine the historical use of Estradiol (E2) as an AD therapy, as well as the outcomes of Randomized Controlled Trials (RCTs) that evaluated antioxidants (e.g., vitamin E) and omega-3 polyunsaturated fatty acids as alternative treatment options. Notably, positive effects of docosahexaenoic acid nutriment in older adults with cognitive impairment or AD are highlighted. Furthermore, this review offers insights into ongoing clinical trials and potential therapies, shedding light on the dynamic research landscape in AD treatment.

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.

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA).

Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to ß-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-ß-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (ß-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded ß-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-ß-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.

Unlocking the potential of PROTACs: A comprehensive review of protein degradation strategies in disease therapy.

The technology known asPROTACs (PROteolysisTArgeting Chimeras) is a method of protein degradation. Utilising bifunctional small molecules, the ubiquitin-proteosome system (UPS) is used to induce the ubiquitination and degradation of target proteins. In addition to being novel chemical knockdown agents for biological studies that are catalytic, reversible, and rapid, PROTACs used in the treatment for disorders like cancer, immunological disorders, viral diseases, and neurological disorders. The protein degradation field has advanced quickly over the last two years, with a significant rise in research articles on the subject as well as a quick rise in smallmolecule degraders that are currently in or will soon enter the clinical stage. Other new degrading technologies, in addition to PROTAC and molecular glue technology, are also emerging rapidly. In this review article, we mainly focuses on various PROTAC molecules designed with special emphasis on targeted cellular pathways for different diseases i.e., cancer, Viral diseases Immune disorders, Neurodegenerative diseases, etc. We discussed about new technologies based on PROTACs such as Antibody PROTAC, Aptamers, Dual target, Folate caged, TF PROTAC, etc. Also, we listed out the PROTACs which are in clinical trials.

Fabrication of chitosan nanocomposites loaded with biosynthetic metallic nanoparticles and their therapeutic investigation.

The present research demonstrates the formation of zinc oxide nanoparticles facilitated by Cissus quadrangularis (CQ-ZnONPs) and subsequent synthesis of chitosan-conjugated nanocomposites (CQ-CS/ZnONCs) along with their biological assessment. The biosynthesized nanoparticles and nanocomposites were physicochemically characterized and therapeutically assessed for their antioxidant, antibacterial, and antidiabetic potential. The formation of CQ-ZnONPs and CQ-CS/ZnONCs was preliminarily validated by the change in color and subsequently by UV-visible spectroscopic analysis. The crystalline peaks associated with the CQ-ZnONPs in CQ-CS/ZnONCs were established by XRD analysis. Morphological evaluation of CQ-ZnONPs and CQ-CS/ZnONCs was carried out through FE-SEM and HRTEM studies. The particle size of the CQ-ZnONPs and CQ-CS/ZnONCs was 243.3 nm and 176.6 nm, with a PDI of 0.188 and 0.199, respectively. Nanoparticles and nanocomposites expressed Zeta potential of -15.7 mV and -16.2 mV, respectively. The CQ-ZnONPs and CQ-CS/ZnONCs showed good radical effectiveness with various in-vitro assays. The formulated nanoparticles and nanocomposites displayed significant antibacterial activity against the selected bacterial pathogens. CQ-CS/ZnONCs presented noteworthy α-amylase and α-glucosidase inhibitory effects compared to CQ-ZnONPs with IC50 of 73.66 ± 1.21 µg/mL and 87.59 ± 1.29 µg/mL, respectively. Moreover, the synthesized CQ-CS/ZnONCs demonstrated 98.92 ± 0.39% and 99.58 ± 0.16% wound contraction (at 7 and 14 mg, respectively), significantly (p < 0.05) higher than the standard and CQ-ZnONPs. Thus, the CQ-ZnONPs and CQ-CS/ZnONCs could effectively develop promising drug delivery systems to inhibit pathogens and chronic tissue repair.

Ethnological validation of Ashwagandha (Withania somnifera L. Dunal) ghrita as 'Vajikarana Rasayana': In-silico, in-vitro and in-vivoapproach.

ETHNOPHARMACOLOGICAL RELEVANCE: Processing cow ghee (clarified butterfat) with therapeutic herbs, i.e. ghrita, is recognized for augmenting the therapeutic efficacy of plant materials. Ashwagandha ghrita (AG) is an effective Ayurvedic formulation consisting of Indian ginseng, i.e., Withania somnifera (L.) Dunal, the main constituent used to treat infertility, weakness, gynaecological disorders, and general debility. OBJECTIVES: The present investigation was undertaken to corroborate the ethnopharmacological claim of AG as 'Vajikarana Rasayana' for its aphrodisiac potential using bioinformatics (in-silico) and experimental (in-vitro and in-vivo) approaches. METHODS: AG was formulated as per the methods reported in Ayurved sarsangraha. AG was further subjected to HPLC, GCMS analysis, and biological (acute toxicity and aphrodisiac) assessment per the standard procedures. Thirty-eight bioactives of Indian ginseng were subjected to computational studies (molecular docking and network pharmacology) to confirm the plausible mechanism. RESULTS: AG was found to be safe up to 2000 mg/kg body wt., and it showed dose-dependent upsurge (p < 0.01 and p < 0.05, wherever necessary) in mount and intromission frequency, genital grooming, and anogenital sniffing at 150 and 300 mg/kg body weight suggesting aphrodisiac activity. In-vitro studies demonstrated significant relaxation of the Corpus Cavernosal Smooth Muscle at all concentrations in a dose-dependent manner. Furthermore, the results of molecular modelling studies were in agreement with the biological activity and showed interaction with phosphodiesterase-5 as a possible target. CONCLUSION: AG exhibited an aphrodisiac effect and substantiated the traditional claim of Indian ginseng-based ghrita formulation as 'Vajikarana Rasayana'.

Preparation, characterization, and evaluation (in-vitro, ex-vivo, and in-vivo) of naturosomal nanocarriers for enhanced delivery and therapeutic efficacy of hesperetin.

The present study intends to formulate, characterize and appraise the phospholipid-based nanovesicular system for enhanced delivery of Hesperetin (HT). The quality by design (QbD) approach was employed to prepare Hesperetin naturosomes (HTN) using the solvent evaporation technique and assessed for physicochemical and pharmacological attributes. The FTIR, DSC, and PXRD studies confirmed the successful formation of a vesicular drug-phospholipid complex, while photomicroscopy, SEM, and TEM analysis revealed the morphology of HTN. The functional attributes substantially enhanced the HT's aqueous solubility, drug release, and membrane permeation. The aqueous solubility of HTN was ~10-fold more than that of pure HT. Likewise, the in-vitro dissolution data of HTN showed better competence in releasing the HT (>93%) than the pure HT (~64%) or the physical mixture (~74%). Furthermore, HTN significantly altered HT permeation (>53%) when compared to pure HT (23%) or the physical mixture (28%). The current study showed that naturosomes are a promising way to improve the solubility in water, bioavailability, and therapeutic effectiveness of drugs.

Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery.

Enoyl acyl carrier protein reductase (InhA) is a key enzyme involved in fatty acid synthesis mainly mycolic acid biosynthesis that is a part of NADH dependent acyl carrier protein reductase family. The aim of the present literature is to underline the different scaffolds or enzyme inhibitors that inhibit mycolic acid biosynthesis mainly cell wall synthesis by inhibiting enzyme InhA. Various scaffolds were identified based on the screening technologies like high throughput screening, encoded library technology, fragment-based screening. The compounds studied include indirect inhibitors (Isoniazid, Ethionamide, Prothionamide) and direct inhibitors (Triclosan/Diphenyl ethers, Pyrrolidine Carboxamides, Pyrroles, Acetamides, Thiadiazoles, Triazoles) with better efficacy against drug resistance. Out of the several scaffolds studied, pyrrolidine carboxamides were found to be the best molecules targeting InhA having good bioavailability properties and better MIC. This review provides with a detailed information, analysis, structure activity relationship and useful insight on various scaffolds as InhA inhibitors.

Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents.

The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives were selected including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6a-j) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one (6c, IC50 - 18.26 to 20.31µM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, IC50 - 18.26 to 20.31µM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis.

Wound with Diabetes: Present Scenario and Future.

Diabetes is a chronic metabolic disorder of the endocrine system characterized by an increase in blood glucose level. Several factors, such as pancreatic damage, oxidative stress, infection, genetic factor, obesity, liver dysfunction, play a vital role in the pathogenesis of diabetes, which further leads to serious diabetic complications. The diabetic wound is one such complication where the wound formation occurs, especially due to pressure and its healing process is disrupted due to factors, such as hyperglycemia, neuropathy, nephropathy, peripheral vascular disease, reduction of blood flow, atherosclerosis, impaired fibroblast. The process of wound healing is delayed due to different abnormalities like alteration in nitric oxide level, increase in aldose reductase, sorbitol, and fructose. Therefore, diabetic wound requires more time to heal as compared to the normal wound. Healing time is delayed in diabetic wound due to many factors, such as stress, decreased oxygenation supply, infection, decreased blood flow, impaired proliferation and migration rate, impaired growth factor production, impaired keratinocytes proliferation and migration, and altered vascular endothelial mediators. The current treatment for diabetic wounds includes wound patches, oxygenation therapy, hydrogel patches, gene therapy, laser therapy, and stem cell therapy. Medications with phytoconstituents are also one way to manage the diabetic wound, but it is not more effective for quick healing. The objective of this review is to understand the potential of various management options which are available for diabetic wound, with a special focus on biological cells.

Effective potential studies for some new hybrid molecules for their activity against prostate cancer / Estudios efectivos de potencial para algunas nuevas moléculas híbridas para su actividad contra el cáncer de próstata

Objective: The present work aimed at developing novel hybrid molecules for targeting the prostate cancer. It is observed that two human shock proteins Hsp70 and Hsp90 are over-expressed in prostate cancer making them one of the important drug targets. We have designed and developed twelve new hybrid molecules 6a-j for targeting these proteins. Methods: The designed molecules were prepared following a four step reaction protocol and characterized on the basis of proton NMR and Mass spectrometry. These were subjected to in vitro studies by means of Oncotest and CCK-8 assays with two cell lines DU145 and 22Rv1. The selected molecules 6b and 6i were subjected to molecular docking and then for SPR based affinity assay. Results: Compounds 6b and 6i were found to be highly active anticancer compounds comparable to standard drug enzalutamide. They have significant IC50 and high dock score for the Hsp70 and Hsp90. These compounds are selective and have good binding affinity for the Hsp70 due to high Kd. Conclusion: Compound 6b and 6i can serve as lead molecules for the development of antiprostate cancer drugs with Hsp70 as target

Objetivo: El presente trabajo tuvo como objetivo desarrollar nuevas moléculas híbridas para atacar el cáncer de próstata. Se observa que dos proteínas de choque humano, Hsp70 y Hsp90, se sobreexpresan en el cáncer de próstata, lo que las convierte en uno de los objetivos farmacológicos importantes. Hemos diseñado y desarrollado doce nuevas moléculas híbridas 6a-j para dirigir estas proteínas. Métodos: Las moléculas diseñadas se prepararon siguiendo un protocolo de reacción de cuatro etapas y se caracterizaron sobre la base de RMN de protón y espectrometría de masas. Estos se sometieron a estudios in vitro por medio de ensayos Oncotest y CCK-8 con dos líneas celulares DU145 y 22Rv1. Las moléculas seleccionadas 6b y 6i se sometieron a acoplamiento molecular y luego a ensayo de afinidad basado en SPR. Resultados: Se descubrió que los Compuestos 6b y 6i son compuestos anticancerígenos muy activos comparables al fármaco estándar enzalutamida. Tienen un IC50 significativo y una puntuación alta para el muelle de Hsp70 y Hsp90. Estos compuestos son selectivos y tienen una buena afinidad de unión por la Hsp70 debido a la alta Kd. Conclusión: Los compuestos 6b y 6i pueden servir como moléculas principales para el desarrollo de fármacos antiprostáticos contra el cáncer con Hsp70 como objetivo

Discovery of Thiazole Based Bis Heterocyclic System for Anti- Inflammatory Potential.

BACKGROUND: We have developed a new series of 36 substituted thiazole derivatives prepared via reaction of substituted benzothiazole-2-amine with substituted phenacyl bromide. OBJECTIVE: This study was aimed to develop and successfully evaluate anti-inflammatory activity of substituted thiazole derivatives. METHOD: A new series of 36 substituted thiazole derivatives was synthesized and derivatives were characterized by analytical and spectrometric methods like IR, MS, and 1H NMR. The molecular docking was performed for all the synthesized thiazole derivatives to assess their binding affinities to COX-2 isozyme. The best compounds from docking study were subjected for their anti-inflammatory activity by using rat hind paw edema method. RESULTS: Results from carrageenan-induced hind paw edema showed that compounds 3h, 5a, 5e, 9d, and 9h possess significant anti-inflammatory activity. The result from vascular permeability indicating inhibition of vascular permeability with compounds 3h and 9h is significant and results from cotton pellet granuloma formation models show greater degree of inhibition with compounds 3h and 5a to contribute to their significant anti-inflammatory activity. CONCLUSION: This study provides successful development of novel thiazole derivatives. Their binding affinities to COX-2 enzyme were also confirmed, indicating that developed molecules are comparable to diclofenac and hence could be promising anti-inflammatory agents.

Dataset of 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole derivatives for GQSAR of antitubercular agents.

Fragment based Quantitative structure activity relationship (QSAR) analysis on reported 25 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole dataset as antitubercular agents were carried out. Molecules in the current dataset were fragmented into six fragments (R1, R2, R3, R4, R5, R6).Group based QSAR Models were derived using Multiple linear regression (MLR) analysis and selected on the basis of various statistical parameters. Dataset of benzothiazole reveled importance of presence of halogen atoms on is essential requirement. The generated models will provide structural requirements of benzothiazole derivatives which can be used to design and develop potent antitubercular derivatives.

Synthesis, antihypertensive activity, and 3D-QSAR studies of some new p-hydroxybenzohydrazide derivatives.

p-Hydroxybenzohydrazide 2 on treatment with aromatic/aliphatic aldehyde followed by cyclization with carbon disulphide afforded compounds 4a-4n. Also, compound 2 by treatment of substituted isothiocyanate followed by the treatment of chloroacetic acid yields the corresponding compounds 6a-6i. All the test compounds were assayed for antihypertensive activity by non-invasive blood pressure measurement and invasive blood pressure measurement methods. The test compounds showed significant antihypertensive activity. The intact compounds were subjected to 3D-QSAR studies. The 3D-QSAR analysis was carried out by PHASE program and a statistically reliable model with good predictive power (r(2) = 0.98, q(2) = 0.74) was achieved. The 3D-QSAR plots illustrated insights into the structure-activity relationship of these compounds which may aid in the design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents.