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Background: Breast cancer is one of the most commonly diagnosed cancer types among women worldwide. Cytochrome P450 aromatase (CYP19A1) is an enzyme in vertebrates that selectively catalyzes the biosynthesis of estrogens from androgenic precursors. Researchers have increasingly focused on developing non-steroidal aromatase inhibitors (NSAIs) for their potential clinical use, avoiding steroidal side effects. Objectives: The objective of the present work is to search for potential lead compounds from the ZINC database through various in silico approaches. Methods: In the present study, compounds from the ZINC database were initially screened through receptor independent-based pharmacophore virtual screening. These screened molecules were subjected to several assessments, such as Lipinski rule of 5, SMART filtration, ADME prediction using SwissADME and lead optimization. Molecular docking was further applied to study the interaction of the filtered compounds with the active site of aromatase. Finally, the obtained hit compounds, consequently represented to be ideal lead candidates, were escalated to the MD simulations. Results: The results indicated that the lead compounds might be potential anti-aromatase drug candidate. Conclusion: The findings provided a valuable approach in developing novel anti-aromatase inhibitors for the treatment of ER+ breast cancer.

Dengue is an arboviral disease caused by the dengue flavivirus. The NS5 protein of flaviviruses is a potential therapeutic target, and comprises an RNA-dependent RNA polymerase (RDRP) domain that catalyses viral replication. The aim of this study was to repurpose FDA-approved drugs against the RDRP domain of dengue virus serotype 3 (DENV3) using structure-based virtual screening and molecular dynamics (MD) simulations. The FDA-approved drugs were screened against the RDRP domain of DENV3 using a two-step docking-based screening approach with Glide SP and Glide XP. For comparison, four reported DENV3 RDRP inhibitors were docked as standards. The hitlist was screened based on the docking score of the inhibitor with the lowest docking score (PubChem ID: 118797902; reported IC50 value: 0.34 µM). Five hits with docking scores and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) energy lower than those of 118797902 were selected. The stability of the hit-receptor complexes was investigated using 100 ns MD simulations in an explicit solvent. The results of MD simulations demonstrated that polydatin and betiatide remained stably bound to the receptor, and formed stable interactions with the RDRP domain of DENV3. The hit-receptor interactions were comparable to those of 118797902. The average Prime MM-GBSA energy of polydatin and betiatide was lower than that of 118797902 during simulation, indicating that their binding affinity to DENV3 RDRP was higher than that of the standard. The results of this study may aid in the development of serotype-selective drugs against dengue in the future. Communicated by Ramaswamy H. Sarma

Epidermal growth factor receptor (EGFR), being one of the most crucial receptor in cancer therapy, has been selected as a potential target for the present study. Ligand-based pharmacophore model (

Our studies show Coomassie Brilliant Blue G-250 as a promising chemical chaperone that stabilises the α-helical native human insulin conformers, disrupting its aggregation. Furthermore, it also increases the insulin secretion....

Abstract In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of β-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein. Graphic Abstract

Introduction: Acetylcholinesterase inhibitors are used to prevent symptoms of Alzheimer’s disease which is initiated due to oxidative stress. Piper betle L. is a tropical evergreen perennial vine whose leaves are widely consumed as masticator in Asia and has medicinal properties. Objectives: The present study is aimed to investigate acetylcholinesterase inhibitory property of methanolic extracts of different varieties of Piper betle leaves and chemometrically identify different bioactive ingredients in vitro and in silico. Materials and Methods: Methanol extracts of the leaves collected in February and October from eight varieties of P. betle (Chhanchi, Bagerhati, Manikdanga, Kalibangla, Bangla, Ghanagete, Meetha and Haldi) were studied for acetylcholinesterase inhibitory properties. Chemical components were analyzed by Gas Chromatography – Mass spectrometry and High Performance Thin Layer Chromatography. Active metabolites were identified chemometrically. The activities were proved in vitro and in silico. Results: All the extracts inhibited acetylcholinesterase. Statistical analysis suggested that several phenolic compounds were correlated to anti-cholinesterase activity. Piceatannol, hydroxychavicol, benzene-1,2,4-triol, and 4-methylcatechol are reported here to have such enzyme inhibitory properties. These four small molecules were further subjected to molecular docking analysis to explore their binding mechanism with the acetylcholinesterase enzyme. All the four small molecules are found to interact with the targeted enzyme in similar fashion like the molecular interactions observed for the standard inhibitor, Donepezil, at the active site of acetylcholiesterase. Conclusion: Thus, consumption of P. betle leaves may have a beneficial effect in the prevention and treatment of this neurodegenerative disease.

Abstract Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as −8.00 and −45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein–ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms. Graphic abstract

Background: Alzheimer’s disease (AD), a neurological disorder, is the most common cause of senile dementia. Butyrylcholinesterase (BuChE) enzyme plays a vital role in regulating the brain acetylcholine (ACh) neurotransmitter, but in the case of Alzheimer’s disease (AD), BuChE activity gradually increases in patients with a decrease in the acetylcholine (ACh) concentration via hydrolysis. ACh plays an essential role in regulating learning and memory as the cortex originates from the basal forebrain, and thus, is involved in memory consolidation in these sites. Methods: In this work, we have developed a partial least squares (PLS)-regression based two dimensional quantitative structure-activity relationship (2D-QSAR) model using 1130 diverse chemical classes of compounds with defined activity against the BuChE enzyme. Keeping in mind the strict Organization for Economic Co-operation and Development (OECD) guidelines, we have tried to select significant descriptors from the large initial pool of descriptors using multi-layered variable selection strategy using stepwise regression followed by genetic algorithm (GA) followed by again stepwise regression technique and at the end best subset selection prior to development of final model thus reducing noise in the input. Partial least squares (PLS) regression technique was employed for the development of the final model while model validation was performed using various stringent validation criteria. Results: The results obtained from the QSAR model suggested that the quality of the model is acceptable in terms of both internal (R2= 0.664, Q2= 0.650) and external (R2 Pred= 0.657) validation parameters. The QSAR studies were analyzed, and the structural features (hydrophobic, ring aromatic and hydrogen bond acceptor/donor) responsible for enhancement of the activity were identified. The developed model further suggests that the presence of hydrophobic features like long carbon chain would increase the BuChE inhibitory activity and presence of amino group and hydrazine fragment promoting the hydrogen bond interactions would be important for increasing the inhibitory activity against BuChE enzyme. Conclusion: Furthermore, molecular docking studies have been carried out to understand the molecular interactions between the ligand and receptor, and the results are then correlated with the structural features obtained from the QSAR models. The information obtained from the QSAR models are well corroborated with the results of the docking study.

Inhibition of aromatase (CYTP450), a key enzyme in the estrogen biosynthesis, could result in regression of estrogen-dependent tumors and even prevent the promotion of breast cancer. The present research has been designed for searching a potent chemical moiety from natural sources to inhibit aromatase enzyme, the overfunctionality of which causes the breast cancer. Cannabis sativa contains a very much promising group of cannabinoids with more than 66 compounds with reported anticancer property and for the search of a target specific potent aromatase inhibitor, 61 cannabinoids from C. sativa were selected. The Structures Data File (SDF) of these ligand molecules were subjected to docking studies at the binding site of aromatase X-ray crystallographic structure based on lower resolution of the protein crystal structure and higher docking accuracy, predicted by calculating the correlation between experimental activities and Glide dock scores and compared with the standard aromatase ligand androstenedione and aromatase inhibitor fadrozole with existing drug for breast cancer treatment. The best docked pose of each ligand was selected on the basis of the highest dock score related to the binding free energies of the internal dataset compounds as compared to their observed activities. Apart from the hydrogen bond formation with the oxygen present on the aromatic ring system, the other parts of the molecules are stabilized by hydrophobic interactions with non-polar amino acid residues (Ile133, Phe134, Phe221, Trp224, Ile305, Ala306, Ala307, Val369, Val370, Leu372, Val373, Met374 and Leu477). From the screening results of the cannabinoid analogs, 21 out of 61 were found to have an acceptable docking score in comparison to the standards, androstenedione and fadrozole. The pharmacokinetic filters like absorption, distribution, metabolism and excretion and toxicity (ADMET) property determination were applied to select drug-like compounds. Among them three compounds were found to reveal the most promising drug like activity, which were cannabidiorcol (CN 17, CBD-C1), cannabitriol (CN 43, CBT) and cannabiripsol (CN 55, CBR). The ani-cancer activity of the target compounds was performed against brine shrimp lethality biassay, where cannabidiorcol exhibited significant LC50 value of 0.348 ±0.002 μg/ml (R² = 0.9853) which is almost similar to vincristine sulfate (LC50 = 0.316±0.003 μg/ml, R² = 0.9882). Compound cannabitriol also showed promisimg cytotoxicity 0.650±0.004 μg/ml (R² = 0.9882) in comparison to the reference standard. But cannabiripsol demostrated relatively weaker activity 12.95±1.234 μg/ml (R²=0.9897). It can be concluded that the lead compounds may be developed as potent aromatase inhibitor performing their further biological evaluation. Dhaka Univ. J. Pharm. Sci. 19(1): 47-58, 2020 (June)

Defense personnel utilize capsaicin-based ocular sprays as non-lethal agents for law implementation during instances of mob violence. This study involves the capsaicin antagonist Capsazepine and th...

Background and purpose Carnitine palmitoyltransferase I (CPT1), an integral outer mitochondrial protein and prime decider of fatty acid β-oxidation (FAO) has been considered to be a key therapeutic target against triple negative breast cancer (TNBC) progression and survival. Herein, we have introduced a biotin-functionalized copolymer, (Py-P(PDSMA-co-PEGMA)-b-P(Bt-PEGMA)), CP4 which can actively target CPT1 and block FAO in metastatic TNBC. Experimental Approach CP4 were synthesized using reversible addition fragmentation chain transfer or RAFT polymerization. In silico computation modelling predicted the active binding of CP4 with CPT1. Cell-based Seahorse energy efflux assay investigated the mitochondrial respiration, glycolytic function and overall ATP production rate. FACS analysis checked the mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) and cell apoptosis. Real-time quantitative reverse transcription PCR (qRT-PCR) analysed FAO-related protein expression profiles. Antitumor activities were confirmed in female breast cancer (BALB/c) mice model. Key results Negative docking score and Ramachandran plot analyses affirmed the active targeting of CP4 to CPT1. Beside, CP4 has remarkably switched the ΔΨm and produced excessive ROS followed by the reduction in glycolytic function, mitochondrial oxidative phosphorylation, FAO and thereby limited excessive ATP production. In turn, it induced metastatic growth inhibition and apoptotic cell death in TNBC cells. Importantly, CP4 has significantly improved the altered lipid and oxidative stress profiles following excellent tumor regression, and thereby advocated plausible FAO-targeted anticancer therapies. Conclusion and Implications CP4 has the potentiality of being a new age FAO-targeted anticancer therapeutics that may open up a new treatment strategy against breast cancer soon.

Sensory irritation is an acute adverse effect leading to temporary disability posed by riot control agents in various deployable forms are utilized by defense personal in violent mob attacks but their irreversible toxic effects and risk assessment have been a matter of concern. These intimidating risks of available riot control agents have led to exploring the pulmonary toxicity profile of the oil in water emulsion formulation developed for vicious crowd controls containing an irritant oleoresin capsicum, a malodorant (skatole), and a commercial dye, followed by characterization using standard methods. Nonlethal riot control combinational formulation (NCF) has been aimed to be the best possible low-lethal alternative for riot control measures. In this study, 30 min of acute inhalation exposure of NCF was given to Wistar rats and various respiratory parameters like lung dynamics, bronchoalveolar lavage fluid (BALF) cytological assays, pro-inflammatory cytokines estimation, antioxidant activity, collagen accumulation, cytotoxicity, in vivo lung imaging, western blot, histology of lung tissue, etc. were investigated to validate its potentiality and rate of irritation reversibility as nonlethal agents. An exaggerated physiological change like sensory irritation, changes in lung functional variables, increased pro-inflammatory cytokines, etc. were noticed initially without airway obstruction as the expression of nociceptive TRPV1 protein did not alter the physiological regulation of protective proteins like Nrf2 and HO-1 and also no abnormality was found in lung tissue architecture. In conclusion, it can be stated that this formulation can be explored as a nonlethal riot control agent intending to generate discomfort but with early reversibility of sensory irritation and no recurrence of toxicity.

Recent evidence concreted that maximum energy in metastatic breast cancer progression is supplied by fatty acid oxidation (FAO) governed by a rate-limiting enzyme, carnitine palmitoyltransferase 1 (CPT1). Therefore, active limitation of FAO could be an emerging aspect to inhibit breast cancer progression. Herein, for the first time we have introduced Quercetin (QT) from a non-dietary source (Mikania micrantha Kunth) to seize the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1. Apart from successive molecular quantification, QT has resulted a significant reduction in the intracellular mitochondrial respiration and glycolytic function limiting extensive ATP production. In turn, QT has elevated the reactive oxygen species (ROS) and depleted antioxidant level to induce anti-metastatic and cell apoptosis activities. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) investigated the FAO associated gene expression resulting significant depletion in FAO which were further confirmed through the successful in-silico molecular docking prediction for active binding potentiality of QT to CPT1. Subsequently, QT has shown an excellent in-vivo antitumor activities through the altered lipid profile and oxidative stress healing capabilities in female breast cancer BALB/c mice model. Therefore, all the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutics.

The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein., Graphical abstract Image 1

We have developed a robust quantitative structure-activity relationship (QSAR) model employing a dataset of 98 heterocycle compounds to identify structural features responsible for BACE1 (beta-secretase 1) enzyme inhibition. We have used only 2D descriptors for model development purpose thus avoiding the conformational complications arising due to 3D geometry considerations. Following the strict Organization for Economic Co-operation and Development (OECD) guidelines, we have developed models using stepwise regression analysis followed by the best subset selection, while the final model was developed by partial least squares regression technique. The model was validated using various internationally accepted stringent validation parameters. From the insights obtained from the developed model, we have concluded that heteroatoms (nitrogen, oxygen, etc.) present within to an aromatic nucleus and the structural features such as hydrophobic, ring aromatic and hydrogen bond acceptor/donor are responsible for the enhancement of the BACE1 enzyme inhibitory activity. Moreover, we have performed the pharmacophore modelling to unveil the structural requirements for the inhibitory activity against the BACE1 enzyme. Furthermore, molecular docking studies were carried out to understand the molecular interactions involved in binding, and the results are then correlated with the requisite structural features obtained from the QSAR and pharmacophore models.

Aim: Simultaneous inhibition of MMP-2 and HDAC8 may be an effective strategy to target cancer. Methodology: In continuation of our earlier efforts, a series of substituted pentanoic acids (1–18) were synthesized and checked for their biological activity along with some earlier reported compounds (19 –35). Results: Compounds 18 and 31 were found to induce apoptosis effectively in a dose-dependent fashion in Jurkat-E6.1 cell line. They reduced the expression of both MMP-2 and HDAC8 effectively. 31 also produced prominent intensity of fluorescence to bring nick in Jurkat-E6.1 cells. 31 also showed cellular arrest in sub-G0 phase. Conclusion: Such compounds may be useful to battle against cancer.

Elevated serum interleukins (IL-6 IL-1beta) over baseline concentration help in blastocyst adhesion to the uterine endometrium in the early phase of pregnancy. A nano PLA (Piperolactam A)-HPBCD (2-hydroxy-propyl-beta-cyclodextrin) inclusion complex was developed as an interleukin down-regulator that exhibited 100% anti-implantation activity in rodents at a dose as low as 2.5-5.0mg/kg. On metabolomics study among major glyco-lipo-protein metabolites only serum low-density lipoprotein (LDL) or very low-density lipoprotein (VLDL) levels revealed alteration by the formulation. Administration of PLA-HPBCD did not cause changes in serum estrogen and progesterone levels. However IL-6 and IL-1beta failed to increase post PLA-HPBCD administration hence is assumed to be the mode of the drugs abortifacient action. In addition absence of signs of either acute or chronic toxicity suggests the formulation considerably non-toxic. Therefore the nano-PLA conjugate promises as a non-steroidal contraceptive lead apart from ormeloxifene the only non-steroidal anti-fertility agent currently available globally. Copyright (c) 2018. Published by Elsevier Inc.

Pharmacoinformatics strategies have been applied to explore promising selective estrogen receptor (ER) modulators (SERMs). A set of non-steroidal ligands was considered for both ERα and ERβ subtypes. Best pharmacophore models revealed with importance of hydrogen bond acceptor and hydrophobicity for both subtypes, along with an aromatic ring and hydrogen bond donor for α and β subtypes, respectively. Both models were validated, and further considered for virtual screening of National Cancer Institute database. Initial hits were sorted with a number of criteria, and finally the molecules have been proposed as promising SERMs. A molecular docking study explained that screened ligands formed a number of binding interactions with both ERs. The subtype receptors in complex with active and screened compounds were considered for molecular simulations to compare stability of the complexes. An analysis of binding energy found that screened ligands hold a strong affinity towards the selective receptor cavity. The proposed ligands might be promising leads for estrogen therapy after experimental validation tests.

This work aimed to reveal the protective mechanism of CA against Dox (doxorubicin)-induced cardiotoxicity. In isolated murine cardiomyocytes, CA showed a concentration-dependent cytoprotective effect against Dox. Dox treatment significantly (p 0.01) increased the formation of reactive oxygen species (ROS), increased NO levels, activated NADPH oxidase, and inactivated the cellular redox defense mechanism in cardiac cells, resulting in augmented oxidative stress in cardiomyocytes and rat hearts. Dox-induced oxidative stress significantly (p 0.01) upregulated several pathogenic signal transductions, which induced apoptosis, inflammation, and fibrosis in cardiomyocytes and murine hearts. In contrast, CA significantly (p 0.05-0.01) reciprocated Dox-induced cardiac apoptosis, inflammation, and fibrosis by suppressing oxidative stress and interfering with pathological signaling events in both isolated murine cardiomyocytes and rat hearts. CA treatment significantly (p 0.05-0.01) countered Dox-mediated pathological changes in blood parameters in rats. Histological examinations backed up the pharmacological findings. In silico chemometric investigations predicted potential interactions between CA and studied signal proteins, as well as the drug-like features of CA. Thus, it would be concluded that CA has the potential to be regarded as an effective agent to alleviate Dox-mediated cardiotoxicity in the future.

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.

Deposition of α–synuclein, tau and β–amyloid protein plaques in brain leads to neurodegeneration. A series of indolin derivatives, which can bind to α–synuclein and detect Parkinson's disease (PD), were used for development of QSAR and QAAR models. It is the first attempt of QSAR for any radiotracer agents used for detection of PD. The binding affinity against α–synuclein was used as dependent variable while independent variables, such as structural, topological, E-state keys, electronic, molecular shape analysis and spatial molecular descriptors were used for QSAR modeling. For QAAR modeling, the binding affinities of molecules for tau and β–amyloid along with different molecular descriptors were used as independent variables. All models were successfully developed using multiple linear regression method, and validated internally and externally, based on different standard criteria. This article describes how the derived models postulate that conformation of molecules and presence of unsaturated hydrocarbon chains, nitro, methoxy and amine functionalities play an important role in determining binding affinity.

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future.

Human insulin (HI) is an essential protein hormone and its biological activity mostly depends on folded and active conformation in the monomeric state. The present investigation established that Coomassie Brilliant Blue G-250 (CBBG), a small multicyclic hydroxyl compound can reversibly bind to the hormonal protein dimer and maintained most of α-helical folds crucial for biological function of the enzyme. The solution-state 1D NMR and isothermal calorimetric analysis showed a sub-micromolar binding affinity of the molecule to HI. 2D NOESY NMR established that the HI dimer undergoes residue level local conformational change upon binding to CBBG. The chemical shift perturbation and the NOE parameters of active protons of amino acid residues throughout the polypeptides further suggested that CBBG upon binding the protein stabilize α-helixes of both the A and B subunits of the hormonal protein. The changes in Gibb’s free energy (∆G) of the binding was of ~−11.1 kcal/mol and suggested a thermodynamically favourable process. The changes in enthalpy (∆H) and entropy term (T∆S) were −57.2 kcal/mol and −46.1 kcal/mol, respectively. The negative changes in entropy and the NOE transfer effectiveness of several residues in the presence of CBBG molecules indicated that the binding was an enthalpy driven favourable equilibrium process. The NMR-based atomic resolution data and molecular docking studies confirmed that the CBBG binds to HI at the dimeric stage and prevents the availability of the crucial residue segments that partake directly in further oligomerization and subsequent fibrillation. Extended computational analysis based on chemical shift perturbation of protons of active residues further established receptor-ligand based pharmacophore model comprised of 5 hydrophobic and a hydrogen bond acceptor features that can anchor the residues at the A and B chains of HI and inhibit the partial unfolding and hydrophobic collapse to nucleate the fibrillation. Taken together, the results demonstrated that CBBG and their close analogues might be useful to develop a formulation that will maintain the active and functional form of the hormonal protein for a significantly longer time.TOC

Defense personnel utilize capsaicin-based ocular sprays as non-lethal agents for law implementation during instances of mob violence. This study involves the capsaicin antagonist Capsazepine and the investigation of whether Capsazepine's antagonistic approach can be favorably utilized for defense utilization to block capsaicin-initiated pain and inflammation via the ocular pathway.Ocular capsazepineA physicochemically stable CapsazepineThe fabricated

Deposition of α–synuclein, tau and β–amyloid protein plaques in brain leads to neurodegeneration. A series of indolin derivatives, which can bind to α–synuclein and detect Parkinson's disease (PD), were used for development of QSAR and QAAR models. It is the first attempt of QSAR for any radiotracer agents used for detection of PD. The binding affinity against α–synuclein was used as dependent variable while independent variables, such as structural, topological, E-state keys, electronic, molecular shape analysis and spatial molecular descriptors were used for QSAR modeling. For QAAR modeling, the binding affinities of molecules for tau and β–amyloid along with different molecular descriptors were used as independent variables. All models were successfully developed using multiple linear regression method, and validated internally and externally, based on different standard criteria. This article describes how the derived models postulate that conformation of molecules and presence of unsaturated hydrocarbon chains, nitro, methoxy and amine functionalities play an important role in determining binding affinity.

Background: Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. Objective: In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. Methods: Insilico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structural-activity relationship (QSAR), pharmacophore mapping and docking studies. Results: It is observed that the presence of an amide fragment (–CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. Conclusion: Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity.

The N-methyl-D-aspartate (NMDA) is the family of glutamate receptor, which is involved in controlling synaptic plasticity and memory function; but overactivation of this receptor results to excess intracellular calcium formation, triggers neuronal injury and also involves in several pathologies. Both ligand- and structure-based quantitative structure-activity relationship (QSAR), pharmacophore, docking and simulation studies have been performed on a set of structurally diverse inhibitors to explore prime molecular structural features involve for specific binding to NMDA, and vis-a-vis inhibiting enzyme activity. 3D QSAR studies, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models showed the importance of steric, electrostatic and hydrophobic features; while hydrogen bond acceptor and hydrophobic features are depicted as important pharmacophore features of the molecule. Molecular docking and simulation studies corroborated the consequence of the features obtained from ligand-based Bayesian model (AUROCcv = 0.878); 3D QSAR CoMFA (R2 = 0.895, se = 0.513, Q2 = 0.602, R2pred = 0.673); CoMSIA (R2 = 0.877, se = 0.555, Q2 = 0.615, R2pred = 0.727); hologram QSAR (Q2 = 0.812, R2 = 0.941, R2pred = 0.772), and pharmacophore models (Q2 = 0.926, R2 = 0.927, R2pred = 0.621). Presence of aromatic ring, hetero and halogen atoms along with alkyl group of molecular scaffold shows their importance for binding affinity to NMDA receptor. Stability of the complex is adjudged by both docking and simulation studies.