Sources and Applications of Tyrosinase in Life Sciences.

BACKGROUND: Tyrosinase, often recognized as polyphenol oxidase, plays a pivotal role as an enzyme in catalyzing the formation of melanin-a complex process involving the oxidation of monophenols and o-diphenols. OBJECTIVE: Tyrosinase functions as a monooxygenase, facilitating the o-hydroxylation of monophenols to generate the corresponding catechols, as well as catalyzing the oxidation of monophenols to form the corresponding o-quinones, exhibiting diphenolase or catecholase activity. This versatile enzymatic capability is not limited to specific organisms but is found across various sources, including bacteria, fungi, plants, and mammals. METHOD: Pertinent research articles, reviews, and patents on tyrosinase were gathered through a comprehensive literature search. These materials were analyzed to gain insights into the diverse applications of tyrosinase. The review was structured by categorizing these applications and offering a thorough summary of the current state of knowledge in the field. RESULT: Based on the literature survey, tyrosinase exhibits promising potential across a spectrum of biotechnological applications. These include but are not limited to: synthesizing L-DOPA, creating innovative mixed melanins, manufacturing phenolic biosensors, deploying in food and feed industries, facilitating protein cross-linking, eliminating phenols and dyes, and serving as a biocatalyst. Moreover, immobilized tyrosinase demonstrates multiple utility avenues within the pharmaceutical sector. CONCLUSION: The article offers a comprehensive exploration of tyrosinase, encompassing its structural features, evolutionary origins, biochemical characteristics, and contemporary applications in various fields.

Exploration of limonoids for their broad spectrum antiviral potential via DFT, molecular docking and molecular dynamics simulation approach.

Limonoids serve as vital secondary metabolites. Citrus limonoids show a wide range of pharmacological potential. As a result of which limonoids from citrus are of considerable research interest. Identification of new therapeutic molecules from natural origins has been widely adopted as a successful strategy in drug discovery. This work mainly focused on the high-throughput computational exploration of the antiviral potential of three vital limonoids, i.e. Obacunone, Limonin and Nomilin against spike proteins of SARS CoV-2 (PDB:6LZG), Zika virus NS3 helicase (PDB:5JMT), Serotype 2 RNA dependent RNA polymerase of dengue virus (PDB:5K5M). Herein we report the molecular docking, MD simulation studies of nine docked complexes, and density functional theory (DFT) of selected limonoids. The results of this study indicated that all three limonoids have good molecular features but out of these three obacunone exerted satisfactory results for DFT, docking and MD simulation study.

Evaluation of curcumin-loaded chitosan nanoparticles for wound healing activity.

Background and purpose: Wound healing is a biological process that can be difficult to manage clinically. In skin wound healing, the interaction of many cells, growth factors, and cytokines reveals an outstanding biological function mechanism. Wound healing that occurs naturally restores tissue integrity, however, it is usually restricted to wound repair. Curcumin synthesised in a chitosan matrix can be used to heal skin sores. Experimental approach: The ionotropic gelation procedure required crosslinking chitosan with a tripolyphosphate (TPP) crosslinker to generate curcumin nanoparticles encapsulated in chitosan. Key results: The nanoparticles were between 200 and 400 nm in size, with a strong positive surface charge and good entrapment efficacy, according to SEM and TEM investigations. Curcumin and chitosan compatibility was investigated using FTIR spectroscopy. All batches showed consistent drug release, with the F5 batch having the highest curcumin release, at 75% after 16 hours. On L929 cells, scratch assays were utilised to assess wound healing. Wound closure with widths of 59 and 65 mm with curcumin and 45 and 78 mm with curcumin-loaded chitosan nanoparticles was seen after 24 and 48 hours of examination. Conclusions: According to the findings, prepared curcumin chitosan nanoparticles are beneficial in healing skin damage.

Glycosylated heterocyles emulsified with antifungal fraction of Moringa oleifera for potentiation of mycolytic activity.

To enhance the clinical effect of antifungal medications for treating deadly fungal infections there is an increasing demand for novel treatments. Exploration of multiple-drug targeting in antifungal therapeutics is the need of the present era. In this pursuit, we identified potent antifungal compounds that were directed towards the multiple virulent targets in Rhizopus arrhizus. Quinoxaline di-N-oxide and piperazine derivatives were identified to exhibit antifungal activities. 03 bioactive compounds were identified from the docking results and antifungal activity. Furthermore, these compounds which were combined with the alkaline extract of M. olifera to make the aqueous phase, an oil phase containing cinnamon oil or clove oil and a combination of surfactants was made to prepare a bioactive composite emulsion. A significant antimycotic activity was seen for the bioactive composite emulsion when compared with the clinically used antifungal drugs. Our results indicate the synergy and potentiation of antimycotic drugs based on integrative medicine.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: An In Silico Molecular Docking and Dynamic Approach.

Over the centuries, cancer has been considered one of the significant health threats. It holds the position in the list of deadliest diseases over the globe. In women, breast cancer is the most common among many cancers and is the second most common cancer all over the world, while lung cancer is the first. Cyclin-dependent kinase 8 (CDK8) has been identified as a critical oncogenic driver that is found in breast cancer and associated with tumor progression. Flavonoids were virtually screened against CDK8 using molecular docking, drug-likeness, ADMET prediction, and a molecular dynamics (MD) simulation approach to determine the potential flavonoid structure against CDK8. The results indicated that ZINC000005854718 showed the highest negative binding affinity of -10.7 kcal/mol with the targeted protein and passed all the drug-likeness parameters. Performed molecular dynamics simulation showed that docked complex systems have good conformational stability over 100 ns in different temperatures (298, 300, 305, 310, and 320 K). The comparison between calculated binding free energy via MM/PB(GB)SA methods and binding affinity calculated via molecular docking suggested tight binding of ZINC000005854718 with targeted protein. The results concluded that ZINC000005854718 has drug-like properties with tight and stable binding with the targeted protein.

In silico evaluation of NO donor heterocyclic vasodilators as SARS-CoV-2 Mpro protein inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 disease has been exponentially increasing throughout the world. The mortality rate is increasing gradually as effective treatment is unavailable to date. In silico based screening for novel testable hypotheses on SARS-CoV-2 Mpro protein to discover the potential lead drug candidate is an emerging area along with the discovery of a vaccine. Administration of NO-releasing agents, NO inducers or the NO gas itself may be useful as therapeutics in the treatment of SARS-CoV-2. In the present study, a 3D structure of SARS-CoV-2 Mpro protein was used for the rational setting of inhibitors to the binding pocket of enzyme which proposed that phenyl furoxan derivative gets efficiently dock in the target pocket. Molecular docking and molecular dynamics simulations helped to investigate possible effective inhibitor candidates bound to SARS-CoV-2 Mpro substrate binding pocket. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed energetic contributions of active site residues of Mpro in binding with most stable proposed NO donor heterocyclic vasodilator inhibitor molecules. Furthermore, principal component analysis (PCA) showed that the NO donor heterocyclic inhibitor molecules 14, 16, 18 and 19 was strongly bound to catalytic core of SARS-CoV-2 Mpro protein, limiting its movement to form stable complex as like control. Thus, overall in silico investigations revealed that 5-oxopiperazine-2-carboxylic acid coupled furoxan derivatives was found to be key pharmacophore in drug design for the treatment of SARS-CoV-2, a global pandemic disease with a dual mechanism of action as NO donor and a worthwhile ligand to act as SARS-CoV-2 Mpro protein inhibitor.Communicated by Ramaswamy H. Sarma.

Discovery of pyridoindole derivatives as potential inhibitors for phosphodiesterase 5A: in silico and in vivo studies.

The aim of this work was to synthesise derivatives from identified plant based pyridoindole lead scaffold, and to assess phosphodiesterase 5A inhibitory potential by in silico and in vivo. Pyridoindole derivatives were synthesised by using six-stage reactor. In silico screening was carried out by grip-based docking methodology. In step-I, tryptophan as a starting material was reacted with different aldehydes and ketones to obtain 11 molecules. In step-II, obtained molecules were reacted with ethanol and benzyl alcohols to obtain D1 to D22 derivatives. In silico investigation resulted in best three molecules D12, D4 and D8 with promising BE score. Oral acute toxicity study of selected molecules resulted in LD50 value 500 mg/kg in rats. The result of in vivo antihypertensive study shown that molecule D12 was found to be the best antihypertensive lead molecule. This study could be a best platform to tailor novel biomolecules for inhibiting phosphodiesterase 5A enzyme in hypertension management.

In silico design and pharmacological evaluation of conjugates of atenolol with modified saccharide for cardiovascular targeting.

Amongst a wide range of biological macromolecules, saccharides exhibit the potential to be specifically recognized by cell-surface receptors and hence can be utilized as ligands in targeted drug delivery. The current study aims to use saccharides viz. Galactose, Pectin and Chitosan to improve targeting of Atenolol by oxalyl chloride mediated grafting. Conjugates were engineered by grafting Atenolol, a cardiovascular agent with the modified saccharide units. The conjugates were characterized by FTIR, DSC and 1H NMR study. Drug release analysis and cellular uptake study was carried out using H9c2 cell lines which represent that concentration of drug in cells treated with all atenolol-saccharide conjugates is enhanced by almost two-folds in comparison with cells treated with atenolol solution. Thus cell line study confers the evidence of selective cardiac delivery. No significant cytotoxicity was observed in case of all synthesized conjugates in the Brine shrimp lethality bioassay. Possible binding of the developed conjugates with the GLUT-4 receptors was assessed by in silico analysis using homology model developed by Swiss Model server. Hence it was concluded that the application of these conjugates with saccharides in selective cardiovascular drug delivery can be a promising approach to increase bioavailability, minimize drug loss by degradation and prevent harmful side effects by increasing specific cell targeting.

Computer Assisted Models for Blood Brain Barrier Permeation of 1, 5-Benzodiazepines.

AIM: To generate and validate predictive models for blood-brain permeation (BBB) of CNS molecules using the QSPR approach. BACKGROUND: Prediction of molecules crossing BBB remains a challenge in drug delivery. Predictive models are designed for the evaluation of a set of preclinical drugs which may serve as alternatives for determining BBB permeation by experimentation. OBJECTIVE: The objective of the present study was to generate QSPR models for the permeation of CNS molecules across BBB and its validation using existing in-house leads. METHODS: The present study envisaged the determination of the set of molecular descriptors which are considered significant correlative factors for BBB permeation property. Quantitative Structure- Property Relationship (QSPR) approach was followed to describe the correlation between identified descriptors for 45 molecules and highest, moderate and least BBB permeation data. The molecular descriptors were selected based on drug-likeness, hydrophilicity, hydrophobicity, polar surface area, etc. of molecules that served the highest correlation with BBB permeation. The experimental data in terms of log BB were collected from available literature, subjected to 2D-QSPR model generation using a regression analysis method like Multiple Linear Regression (MLR). RESULTS: The best QSPR model was Model 3, which exhibited regression coefficient as R2= 0.89, F = 36; Q2= 0.7805 and properties such as polar surface area, hydrophobic hydrophilic distance, electronegativity, etc., which were considered key parameters in the determination of the BBB permeability. The developed QSPR models were validated with in-house 1,5-benzodiazepines molecules and correlation studies were conducted between experimental and predicted BBB permeability. CONCLUSION: The QSPR model 3 showed predictive results that were in good agreements with experimental results for blood-brain permeation. Thus, this model was found to be satisfactory in achieving a good correlation between selected descriptors and BBB permeation for benzodiazepines and tricyclic compounds.

Development of lipoprotein-drug conjugates for targeted drug delivery.

Tumour targeting approaches used in cancer chemotherapy offers prolonged, localized, and protected drug interaction with the diseased tissue with minimal side effects and systemic toxicity, which are accountable for the failure of chemotherapy using conventional delivery systems. The purpose of the present study is to develop an anticancer targeted drug delivery system using synthesized lipoproteins with the integration of quality by design approach. Lipoprotein structures were designed, and quality by design approach was implemented to select variables for optimization. Further, the lipoproteins were synthesized and characterized by physicochemical properties. Physical composites of synthesized lipoproteins with the drug (tablets) were prepared and evaluated for post-compression parameters. Moreover, drug-lipoprotein chemical conjugates were synthesized and characterized for physicochemical properties, including cellular drug uptake and cytotoxicity study on HaCaT cancer cells. Synthesized lipoproteins showed good swelling capacity but poor flowability. Nuclear magnetic resonance and infrared spectroscopy of conjugates showed characteristic peaks. Tablets from all batches extended the drug release up to 12 h. All synthesized conjugates showed improved cellular drug uptake (up to 86.1%) and inhibition (87.39%) of HaCat cancer cells. These findings explored the possible use of synthesized lipoproteins in the development of anti-cancer drug formulation against HaCat cancer cells.Communicated by Ramaswamy H. Sarma.

Identification and Investigation of Chalcone Derivatives as Calcium Channel Blockers: Pharmacophore Modeling, Docking Studies, In vitro Screening, and 3D-QSAR Analysis.

BACKGROUND: The chalcones were reported to have many biological activities by showing affinity towards many enzymatic targets. The effect of nitric oxide (NO) on calcium channel was extensively studied in different animals; the study was also carried out for NO donor drug and its effect on calcium channel. Till date, the inhibition of calcium channel is of prime importance in the medicinal chemistry to discover newer vascular smooth muscle relaxant drugs. OBJECTIVE: The main objective of this work is to carry out in silico and in vitro evaluation of NO donor chalcones for calcium channel blocking potency. METHODS: The present work includes in silico evaluation of chalcone derivatives for calcium channel blocking potency. The promising scaffolds were identified after pharmacophore modeling and docking study. The in vitro screening of 21 lead molecules for calcium channel blocking potency was carried out on pulmonary veins of adult goat, IC50 values were determined and 3D QSAR was performed. RESULTS: The pharmacophore modeling revealed that hydrogen bond donor, hydrogen bond acceptor, and hydrophobic groups are important features for calcium channel blocking activity. The docking study revealed the existence of hydrophobic, hydrogen bond and Vander wall's interactions between amino acid residues and ligands. The in vitro screening showed that the compounds AI6, Ca2, and D8 were potent, produced 4.756, 3.608 and 5.211 µM of IC50 respectively, whereas the standard Nifedipine showed the potency of 1.304 µM of IC50. The 3D QSAR study explained the importance of different steric and electrostatic parameters and their correlation for L type calcium channel blocking activity. CONCLUSION: This study showed that the chalcone scaffold with NO donor capacity is promising for designing novel calcium channel blockers to treat vascular disorders.

Synthesis and Modeling Studies of Furoxan Coupled Spiro-Isoquinolino Piperidine Derivatives as NO Releasing PDE 5 Inhibitors.

Nitric oxide (NO) is considered to be one of the most important intracellular messengers that play an active role as neurotransmitter in regulation of various cardiovascular physiological and pathological processes. Nitric oxide (NO) is a major factor in penile erectile function. NO exerts a relaxing action on corpus cavernosum and penile arteries by activating smooth muscle soluble guanylate cyclase and increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). Phophodiesterase (PDE) inhibitors have potential therapeutic applications. NO hybridization has been found to improve and extend the pharmacological properties of the parental compound. The present study describes the synthesis of novel furoxan coupled spiro-isoquinolino-piperidine derivatives and their smooth muscle relaxant activity. The study reveals that, particularly 10d (1.50 ± 0.6) and 10g (1.65 ± 0.7) are moderate PDE 5 inhibitors as compared to Sidenafil (1.43 ± 0.5). The observed effect was explained by molecular modelling studies on phosphodiesterase.

Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials.

BACKGROUND: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance. OBJECTIVES: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design. METHODS: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures. RESULTS: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity. CONCLUSION: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Vasorelaxant Effect of Novel Nitric Oxide-Hydrogen Sulfide Donor Chalcone in Isolated Rat Aorta: Involvement of cGMP Mediated sGC and Potassium Channel Activation.

BACKGROUND AND OBJECTIVE: Recently, nitric oxide (NO) and hydrogen sulfide (H2S) donating moieties were extensively studied for their role in the vasculature as they are responsible for many cellular and pathophysiological functioning. The objective of the present study is to evaluate novel NO and H2S donating chalcone moieties on isolated rat aorta for vasorelaxation, and to investigate the probable mechanism of action. METHODS: To extend our knowledge of vasorelaxation by NO and H2S donor drugs, here we investigated the vasorelaxing activity of novel NO and H2S donating chalcone moieties on isolated rat aorta. The mechanism of vasorelaxation by these molecules was investigated by performing in vitro cGMP mediated sGC activation assay and using Tetraethylammonium chloride (TEA) as a potassium channel blocker and Methylene blue as NO blocker. RESULTS: Both NO and H2S donating chalcone moieties were found to be potent vasorelaxant. The compound G4 and G5 produce the highest vasorelaxation with 3.716 and 3.789 M of pEC50, respectively. After the addition of TEA, G4 and G5 showed 2.772 and 2.796 M of pEC50, respectively. The compounds Ca1, Ca2, and D7 produced significant activation and release of cGMP mediated sGC which was 1.677, 1.769 and 1.768 M of pEC50, respectively. CONCLUSION: The vasorelaxation by NO-donating chalcones was blocked by Methylene blue but it did not show any effect on H2S donating chalcones. The vasorelaxing potency of NO-donating molecules was observed to be less affected by the addition of TEA but H2S donors showed a decrease in both efficacy and potency. The cGMP release was more in the case of NO-donating molecules. The tested compounds were found potent for relaxing vasculature of rat aorta.

Quantitative Structure-Property Relationship Approach in Formulation Development: an Overview.

Chemoinformatics is emerging as a new trend to set drug discovery which correlates the relationship between structure and biological functions. The main aim of chemoinformatics refers to analyzing the similarity among molecules, searching the molecules in the structural database, finding potential drug molecule and their property. One of the key fields in chemoinformatics is quantitative structure-property relationship (QSPR), which is an alternative process to predict the various physicochemical and biopharmaceutical properties. This methodology expresses molecules via various numerical values or properties (descriptors), which encodes the structural characteristics of molecules and further used to calculate physicochemical properties of the molecule. The established QSPR model could be used to predict the properties of compounds that have been measured or even have been unknown, which ultimately accelerates the development process of a new molecule or the product. The formulation characteristics (drug release, transportability, bioavailability) can be predicted with the integration of QSPR approach. Therefore, QSPR modeling is an emerging trend to skip conventional drug as well as formulation development process. The current review highlights the overall process involved in the application of the QSPR approach in formulation development.

Synthesis, Antimicrobial Evaluation and Molecular Docking of Some Potential 2,6-disubstituted 1H-Benzimidazoles; Non-Classical Antifolates.

BACKGROUND: Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time, some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR. OBJECTIVE: Our goal behind present investigation is to explore benzimidazoles class of drugs as microbial DHFR inhibitors by studying ligand-receptor binding interactions, in vitro enzyme inhibition assay and confirmation of anti-microbial activity against selected pathogenic microorganisms. METHODS: A library containing thirty novel 2,6-disubstituted 1H-benzimidazoles was synthesized by one pot condensation of o-nitro aniline or 2,4-dinitro aniline with series of aldehydes or acetophenones using Na2S2O4 or SnCl2 respectively and reflux for 5-6hr. Structures of compounds have been confirmed by spectroscopic methods as 1H and 13C NMR, FT-IR and MS. In vitro DHFR inhibition study was performed by using Epoch microplate reader and IC50 of the test compounds was compared with Trimethoprim. In vitro antimicrobial activity was performed against selected clinical pathogens by agar disk diffusion method and MIC (µg/mL) was reported. RESULTS: Moderate to good level of DHFR inhibition was observed with IC50 values in the range of 7-23 µM. Compounds B1, B19, B22, B24 and B30 expressed 1.1 to 1.4 folds more prominent DHFR inhibitory activity as compared to standard Trimethoprim. Remarkable antimicrobial activity was exhibited by B1, B19, B22, B24 and B30. Molecular docking study revealed perfect binding of test ligands with key amino acids of DHFR as Phe31, Ile94, Ile5, Asp27, Gln32 and Phe36. CONCLUSION: Nature of 1H-benzimidazole substituents at position 2 and 6 had influence over magnitude and type of molecular binding and variation in the biological activity. The present series of 1H-benzimidazoles could be considered promising broad-spectrum antimicrobial candidates that deserve in future for preclinical antimicrobial evaluation and development of newer antimicrobial agents targeting microbial DHFR.

Investigation of anti-inflammatory, nitric oxide donating, vasorelaxation and ulcerogenic activities of 1, 3-diphenylprop-2-en-1-one derivatives in animal models.

The main aim of this work is to find out novel chemical moieties with potent anti-inflammatory and vasorelaxant activities with reduced gastric toxicities. For fulfilling the above aim, here we investigated novel chalcones (1, 3-diphenylprop-2-en-1-one derivatives) with nitric oxide (NO) and hydrogen sulphide (H2 S) donating potency for anti-inflammatory activity by carrageenan-induced rat paw oedema. These molecules then further evaluated for in-vitro NO-releasing potency and vasorelaxation effect on isolated adult goat aortic tissue. The promising molecules were further screened for ulcerogenic activity in the rat model. The tested compounds produced % inhibition in paw oedema ranging from 29.16% to 79.69% and standard drug Diclofenac sodium produced 85.30% reduction in paw oedema after 5 hours. Out of this dataset, compounds AI1, AI7, Ca1, B2, B10, D2, and E8 showed 73.01%, 79.69%, 75.02%, 75.46%, 74.35%, 73.9% and 74.35% reduction in paw oedema respectively, which is approximately 80%-90% to that of standard Diclofenac sodium. The compound Ca1 was found to release 0.870 ± 0.025 mol/mol of NO and standard Glyceryl trinitrate (GTN) was found to release 0.983 ± 0.063 mol/mol of NO. The compound Ca1 produced 950.2 µmol/L of EC50 whereas standard GTN produced 975.8 µmol/L of EC50 for aortic smooth relaxation. The compounds Ca1 produced 0.1117 of ulcer index which is far less than that of standard Diclofenac sodium (1.148). The potent lead molecules were further evaluated to understand the mechanism of vasorelaxation by using specific antagonists or blockers of NO and H2 S.

Development of leads targeting ER-α in breast cancer: An in silico exploration from natural domain.

The steroid, estrogen has been recognized as being important for stimulating the growth of breast cancers primarily mediated via the steroidal estrogen receptor-α (ER-α). Inhibition of estrogen activity by small molecules with increased target specificity has proven to be an effective treatment for breast cancer. After the success stories of SERMs and fulvestrant, there is a need for the development of new small molecule modulating ER-α is due to developing resistance and side effects to current breast cancer therapy. In this pursuit, we virtually screened 227 chemically diverse bioactive natural products to get the best hits having an ER-α binding affinity. The docking scores and protein-ligand interactions of the obtained hits were emulated with the clinically used selective estrogen modulators and ER-antagonists. The results revealed 18 potential hits, which were putatively classified as hits belonging to ER agonists, modulators, and antagonists. Furthermore, as most of the hits were found to comprise the chromene nucleus, the 2D and 3D QSAR studies were performed using a set of natural products and synthesized compounds containing this scaffold, to understand the structural requirements for improving activity against breast cancer. Additionally, a pharmacophore model was generated to investigate the pharmacophoric features of the explored scaffolds for an optimal anticancer activity. The results signify that these compounds with structural modification could serve as potential leads in the drug discovery process for the treatment of breast cancer.