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The cognitive science of religion (CSR) seeks to find causal explanations for the origin, dissemination and transmission of theistic beliefs. One of the beliefs related to the field of religion is counterintuitive concepts: ideas and concepts that violate the automatic and non-reflective expectations of our mental tools. According to the researchers of CSR, counterintuitive concepts, if they are used in their minimal sense and do not weaken the conceptual coherence, cause the permanence and transmission of religious beliefs in comparison with other beliefs. Therefore, counter intuitiveness plays an important role in understanding religion. Despite the positive points of counterintuitive concepts, we believe that these concepts have ambiguities and problems that, if not properly explained and corrected, will cause problems in the acceptance and fixation of theistic beliefs: First, metare presentation's inability to solve the problem of distinguishing between counterintuitive religious beliefs and other counterintuitive concepts. Second, ambiguity in the explanatory role of counterintuitive concepts. Third, emphasis on cognitive architecture and not paying attention to the role of upbringing and culture in identifying counterintuitive concepts. Fourth, the inconsistency in the analysis of some counterintuitive concepts such as God with the official doctrine of religions. Fifth, not paying attention to conscious intuitions. Sixth, it seems that with the naturalization of beliefs in the cognitive system, human agents will take the place of supernatural agents, but the statistics show something else. [ABSTRACT FROM AUTHOR]

This article presents research on the synthesis and evaluation of new compounds as potential anticancer agents. The compounds, derived from N-(benzo[d]thiazol-2-yl)-3-amino-but-2-enamide, were synthesized and characterized using various techniques. Molecular modeling and docking studies were conducted to understand their interactions with DNA. The compounds showed significant cytotoxic activity against lung cancer cells, with one compound being particularly effective. The authors acknowledge the support they received from the National Institute for Medical Research Development. [Extracted from the article]

To examine Putnam's views on the application of quantum logic is the aim of this paper. Hilary Putnam defends quantum logic in his works. According to him, classical logic cannot answer the problems arising in quantum mechanics. Therefore, we need to present a non-classical logic, namely quantum logic. Putnam argues three main reasons for the transition from classical logic to quantum: I. to be false some of the necessary truths of logic, II. have to change of logic, III. the pattern of three-valued logic. Putnam's views about this transition to quantum logic can be considered from several points: First, despite Putnam's criticism of classical logic, he defends quantum logic through the rules of classical logic. Second, it is a bulky claim to know of quantum logic as "true" logic. Third, the conclusions of the Cartesian product have changed in Putnam's analysis. Fourth, in his logic system, Putnam pays attention to "intuition" instead of relying on "axioms." Fifth, the middle value of truth is ineffective and erroneous in quantum logic. Despite these criticisms, many of them can be answered analytically. [ABSTRACT FROM AUTHOR]

Seventeen new xanthene-1,8-dione derivatives were synthesized and evaluated as cytotoxic agents against the lung carcinoma cell line (A549). Compound 9-(4-(benzyloxy)phenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (4a) showed good cytotoxic effects (34.59 μM) in comparison to cis-platin. Docking results showed 4a could interact with DNA as intercalation. Calculated ligand efficiency of compound 4a was more than daunomycin. Based on the results, it can be concluded that compound 4a is a suitable DNA binding agent. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a destructive neurological disease. Approved therapies that target the cholinergic system to control the symptoms have various complications. Natural compounds that inhibit the acetylcholinesterase (AChE) enzyme can promote the development of new drugs. Nature‐derived compounds are more compatible with biological systems in comparison to synthetic library. Ferula haussknechtii is a native species of Iran. In study, we evaluated the effects of its essential oil and extracts on the inhibition of AChE through in vitro and in silico methods. The essential oil was extracted by Clevenger apparatus. Extracts were prepared by maceration for 72 hours. The Ellman's test was used to measure the inhibitory effects of the samples. The interaction of the main constituents of the essential oil with AChE was investigated by Coarse Grained molecular dynamics (CG‐MD) simulation. Essential oil inhibited the AChE with IC50: 44.6 μg/ml. Among different extracts, hydroalcoholic extract with IC50: 41.4 μg/ml exhibited the most potent inhibitory effect. Based on the results of 1 μs CG‐MD simulation, the major constituents of the essential oil inhibited the AChE by binding to the PAS site. The constituents of F. haussknechtii could be considered as a rich source for discovering and designing new AChE inhibitors. [ABSTRACT FROM AUTHOR]

The goal of science is to explain reality and the world, and the goal of philosophy is also ontology. Philosophical views on scientific opinions and scientific opinions have had a direct influence on the way of worldview and ontology. Since the early twentieth century, the scientific flow of reduction affects logic and philosophy, psychology and sociology, and even theology and religion. On the other hand, the new emergent flow of emergentism in opposition to reductionism flourished in the late twentieth century. The philosophical and analytical validation of these two seemingly contradictory views promotes the levels of scientific methods and approaches, as well as philosophical views, especially philosophies such as the philosophy of religion, the philosophy of psychology, and the philosophy of sociology. Reductionism is trying to coordinate with unity, realize the unity of sciences, eliminate the waste of scientific theories, and provide the possibility of a stronger justification. On the other hand, emergentism involves the hierarchical plurality of the world's creatures. On the other hand, emergentism involves the hierarchical plurality of the world's creatures which causes the classification of science. Each level and class have its lows, rules, and concepts per se. Reductionism is unable to explain the plurality of facts and levels of existence; But emergentism with its theoretical framework explains both the continuum, unity and multiplicity of reality means the hierarchical plurality of reality. the reduction merely is an essential step in understanding and discovering down-up causality that is used as one of the theoretical concepts of emergentism and somewhat explains the cause of the relationship between the layers of existence. But reduction strategy is not successful in recognizing and explaining the existence of layers and classes of science. Reductions with a priority look at reality are subject to selfish judgment and preference, but in emergentism, reality and ontology determine and identify the methodology and epistemology. [ABSTRACT FROM AUTHOR]

Cancer disease is developing all over the world mainly in developing countries. We should learn more about DNA–ligand interactions to design new drugs that target biological activities like transcription, replication and translation of particular genes. To understand the mechanism of action and design-specific DNA binders, the evaluation of DNA–ligand interactions is critical. Novel barbituric acid derivatives based on (benzyloxy)benzaldehydes were synthesized and evaluated as DNA-binding agents. Among products, molecular docking studies revealed that 4j and 4m have the best interactions with the ctDNA via the minor groove binding. These results were approved by the quantum mechanics calculations. The interaction profiles of the selected compound (4j and 4m) with DNA were evaluated by UV–Visible titration. UV–Visible titration data confirm this interaction. According to the molecular modeling results, the Structure–Activity relationships for all synthesized barbituric acid derivatives were proposed. It was observed that N,N-dimethyl barbituric acid/4-hydroxybenzaldehyde derivatives have better DNA interactions than barbituric acid/vanillin and barbituric acid/3-hydroxybenzaldehyde derivatives. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide. Drug researchers have encouraged by the growth of cancer incidence and low efficacy of current treatment to discover new drugs. Targeting specific regions of DNA to turn on/off genes has become an interesting research area. We evaluated the interaction of 5-(benzylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives with ctDNA using in vitro and in silico studies. MD simulation indicated that selectivity switched from AT to CG-rich DNA strands when the chloro substitution was moved from meta to para position of the phenyl ring. 4-OH derivative showed similar affinity to AT and CG-rich DNA strand. Quantum mechanics calculation indicated that 4-OH derivative had the highest HOMO energy. The order in HOMO energies was compatible with the absorption titration result that demonstrated the order of Ka as 4-OH > 4-Cl > 3-Cl. Synopsis. 5-(benzylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives could interact with ctDNA. MD simulation indicated that m- and p-chlorophenyl derivatives selectively bind to AT and CG-rich DNA strands respectively. The order in HOMO energies was compatible with absorption titration result that demonstrated the order of Ka as 4-OH > 4-Cl > 3-Cl. [ABSTRACT FROM AUTHOR]

According to property-emergentism, consciousness is an emergent property of certain aggregate neurological constructions, whereas substance-emergentism maintains that the emergence of consciousness depends on the emergence of mental substance or soul. In this article, we presented some arguments supporting substance-emergentism by analysing various properties of consciousness, including the first-person perspective, referral state, qualia, being active, causative, non-atomic, interpretative, inferential and inventive (emanative and innovative). We also explored the impossibility of representing big images on the small monitor and the incapacity of physical entities being conscious because of their intrinsic multiplicity, absence and deficiency. These arguments, which apply the philosophy of Mulla Sadra, could be considered by philosophers of mind and religion, as well as theologians who follow some religious beliefs such as the afterlife on existence and survival of the soul. Also, we attempted to respond to property-emergentists' objections to substance-emergentism. [ABSTRACT FROM AUTHOR]

Background. Adenoidectomy is the most common way to stimulate the vagus nerve, and ultimately bradycardia. Objectives. The aim of this study was to determine the incidence rate of bradycardia caused by nasopharynx irritation and its related factors in patients undergoing adenoidectomy surgery. Material and methods. The current study is a descriptive-analytic cross-sectional study. 142 children under adenoidectomy surgery enter the study in 2017. Demographic data, hemoglobin, echocardiography, SpO2, heart rate of patient before and after anesthesia and during and after surgery, duration of surgery, use or non-use of atropine and its amount were collected. Sampling was carried out using the sequential non-probabilistic method. SPSS version 22 was used to analyze the data. Results. The average age was 3.1 years. The rate of bradycardia among 1 to 2-year-old patients was 38.8% (14 patients) and among 2 to 6-year-old patients it was 12.4% (13 patients). The results of 1 to 2-year-old patients showed a significant relationship between bradycardia and age. The results of 2 to 6-year-old patients showed a decrease in bradycardia as age increases to 6 years. There was a significant relationship between bradycardia and SpO2 rate at the ages of 1 to 2 years and 2 to 6 years. With bradycardia, the patient SpO2 dropped. There was a significant relationship between bradycardia and duration of surgery, and also atropine use. Conclusions. Due to the occurrence of early bradycardia in early ages in adenoidectomy and the possibility of affecting the cardiac output, more precision during this surgery by anesthesiologists and surgeons leads to a reduction in adverse bradycardia effects on the heart. [ABSTRACT FROM AUTHOR]

■ Some new coumarin-fused 4 H -pyran derivatives were synthesized and evaluated as α-glucosidase inhibitors. ■ Compound 6e showed the most potent inhibitory activity (IC 50 = 30.05 µM) in comparison with acarbose as a standard inhibitor (IC 50 = 750.0 µM). ■ Molecular dynamic simulation and kinetic studies showed compound 6e bound to key amino acids of the active site as a competitive inhibitor. Some new coumarin-fused 4 H -pyran derivatives were synthesized and assessed against yeast α-glucosidase enzyme. All of the synthesized compounds showed significant inhibitory activity towards the enzyme with IC 50 values in range of 30.05 ± 0.5–274.3 ± 1.0 μM in comparison with acarbose, as a standard agent (IC 50 = 750.0 μM). Among them, 4-(4-(4-bromobenzyloxy)-3-methoxyphenyl)-2-amino -4,5-dihydro-5-oxopyrano[3,2- c ]chromene-3-carbonitrile (compound 6e) indicated the most potent inhibitory activity. The kinetic study of the compound 6e revealed that this compound inhibited α-glucosidase in a competitive pattern. Homology modeling was utilized to determine 3D structure of the α-glucoside enzyme. Afterwards, the molecular docking and dynamic simulation studies confirmed successful placement of the compound 6e in the active site of α-glucosidase. Besides, the R - and S - enantiomers of the compound 6e showed significant interactions with the catalytic triad residues (Asp214, Glu276, Asp349). The results of in silico prediction study for ADME also indicated that these coumarin-fused 4 H -pyran derivatives have acceptable pharmacokinetic and potential therapeutic benefits for the future treatment of type 2 diabetes mellitus (T2DM). [ABSTRACT FROM AUTHOR]

Chemokine receptor 2 (CCR2), a G-protein coupled receptor (GPCR), is a critical target for several inflammatory and autoimmune diseases. The main restriction on designing desirable antagonists against CCR2 is the lack of appropriate crystal structure for this target. In the absence of such experimental data, computational methods triggering structure prediction provide a cost-effective option. Homology modeling has been widely used to explore GPCR structure. Within the present contribution, homology modeling, molecular docking and molecular dynamics (MD) simulation were applied to construct a reliable model for CCR2. In the present contribution, we docked INCB3344, one of the most potent CCR2 inhibitors, into the active site of the CCR2 protein. Subsequently, we studied the dynamic behavior of INCB3344-CCR2 complex in the presence of lipid membrane. Moreover; a detailed molecular mechanism of INCB3344 action has been proposed. It was revealed that Tyr120, His121, Tyr259 and Glu291 formed H-bond interactions with INCB3344 while residues such as Trp98, His202, Thr203 and Thr173 participated in hydrophobic interactions. As a consequence, a reliable homology model of CCR2 could be successfully developed on the basis of CCR5 crystallographic structure. Finally it was found that binding of INCB3344 led to the structural changes in CCR2 that provided more interaction sites. Results of this study may be useful to design further CCR2 inhibiting structures with the aim of developing desirable therapeutic agents. [ABSTRACT FROM AUTHOR]

• Benzylidene 6-methoxy-1-tetralone linked to benzyloxy and benzyl-1,2,3- triazole rings derivatives were designed, synthesized and evaluated as potential tyrosinase inhibitors. • All compounds were evaluated for their tyrosinase inhibitory activities. • Compound 7d showed the most potent anti-tyrosinase activity (IC 50 = 4.64 µM). • Molecular modeling and kinetic studies showed compound 7d bound to amino acids around the entrance of the active site as an uncompetitive inhibitor. Novel benzylidene 6-methoxy-1-tetralone derivatives linked to benzyloxy- and benzyl -1,2,3- triazole rings were designed, synthesized, and evaluated as potential tyrosinase inhibitors. The products can be divided into two groups: Benzyloxy-benzylidene-6-methoxy-1-tetralone and Benzyl-1,2,3-triazole-benzylidene-6-methoxy-1-tetralone derivatives. Some of them showed acceptable activities against mushroom tyrosinase enzyme. Among them, (E)-2-(4-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzylidene)-6-methoxy-3,4-dihydronaphthalen-1(2 H)-one (7d) containing 1,2,3-triazole ring and 3-chlorine at the benzyl pendant moiety indicated significant anti-tyrosinase activity with an IC 50 value of 4.64 μM which was better inhibitory activity than kojic acid as reference compound (19.26 μM). The molecular modeling studies demonstrated that the compound 7d could occupy the adjacent pocket to the binding site. Compound 7d interacted with the loop (Ile184-Asp191) through its 6-methoxy-3,4-dihydronaphthalen-1(2 H)-one moiety that oriented the 3-clorophenyl group to the entrance of binding site. Kinetics study showed compound 7d acts as an uncompetitive inhibitor and molecular modeling conformed results. In silico ADMET studies predicted that these products have good drug-likeness. All findings indicate that compound 7d has good potential for the inhibition of melanogenesis compared to kojic acid. [Display omitted] [ABSTRACT FROM AUTHOR]

Chemotherapy Induced Nausea and Vomiting (CINV) is among the most intensive side effects and critical concerns for patients with cancer. Most of these patients experience nausea and vomiting after chemotherapy. Sometimes, this is so annoying that it may prevent them from continuing the therapy. With the recent advances, a variety of therapeutic methods are innovated and applied to control CINV. Among them, the main methods include medicinal therapy, relaxation, and herbal therapy. Yet, using dexamethasone together with massage therapy and ginger is identified as the most effective method. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor-2 (VEGFR-2); a cell surface receptor for vascular endothelial growth factors, is a key pharmacological target involved in the cell proliferation/angiogenesis. It has been revealed that VEGFR-2 induces proliferation through activation of the extracellular signal-regulated kinases pathway. In this regard, targeting the VEGFR-2 has been considered as an efficient route to develop anti-tumor agents. Motesanib is a small-molecule antagonist of VEGFR-1, 2, and 3 (IC50s; 2 nM, 3 nM, 6 nM, respectively). It is an experimental drug candidate undergoing clinical trials against some types of cancer. In the present study, Motesanib (AMG 706) was evaluated in terms of its binding energies with individual amino acids of VEGFR-2 active site (amino acid decomposition analysis). For this purpose, functional B3LYP associated with split valence basis set using polarization functions (Def2-SVP) was used. Comparative conformational analysis of the ligand in optimized and crystallographic states revealed that Motesanib does not necessarily bind to the VEGFR-2 active site in its minimum energy conformer. [ABSTRACT FROM AUTHOR]

Background and purpose of the study: p38α is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases. Several small molecule p38α inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead development strategies. Methods: Various interactions of three potent inhibitors with p38á active site have been evaluated in terms of binding energies and bond lengths via density function theory and MD simulations. Results: Our comparative study showed that both ab initio and MD simulation led to the relatively similar results in pharmacophore discrimination of p38α inhibitors. Conclusion: The results of the present study may find their usefulness in pharmacophore based modification of p38á inhibitors. [ABSTRACT FROM AUTHOR]

Computational evaluation of ligand-receptor binding via docking strategy is a well established approach in structure-based drug design. This technique has been applied frequently in developing molecules of biological interest. However, any procedure would require an optimization set up to be more efficient, economic and time-saving. Advantages of modern statistical optimization methods over conventional one-factor-at-a-time studies have been well revealed. The optimization by experimental design provides a combination of factor levels simultaneously satisfying the requirements considered for each of the responses and factors. In this study, response surface method was applied to optimize the prominent factors (number of genetic algorithm runs, population size, maximum number of evaluations, torsion degrees for ligand and number of rotatable bonds in ligand) in AutoDock4.2-based binding study of small molecule β-secretase inhibitors as anti-alzheimer agents. Results revealed that a number of rotatable bonds in ligand and maximum number of docking evaluations were determinant variables affecting docking outputs. The interference between torsion degrees for ligand and number of genetic algorithm runs for docking procedure was found to be the significant interaction term in our model. Optimized docking outputs exhibited a high correlation with experimental fluorescence resonance energy transfer-based ICs for β-secretase inhibitors (R = 0.9133). [ABSTRACT FROM AUTHOR]

Objectives: To examine the role of anesthetists in the management of cardiac arrest occurring in association with cardiac anesthesia. Methodology: In this retrospective study we studied the potential performances for each of the relevant incidents among 712 patients undergoing cardiac operations at Golestan and Naft Hospitals Ahwaz between November 2006 and July 2008. Results: Out of total 712 patients undergoing cardiac surgery, cardiac arrest occurred in 28 cases (3.9%) due to different postoperative complications. This included massive bleeding (50% of cardiac arrest cases, 1.9% of patients); pulseless supra ventricular tachycardia (28.5% of cardiac arrest cases, 1.1% of patients); Heart Failure (7% of cardiac arrest cases, 0.2% of patients); Aorta Arc Rapture (3.5% of cardiac arrest cases, 0.1% of patients); Tamponade due to pericardial effusion (3.5% of cardiac arrest cases, 0.1% of total patients); Right Atrium Rupture (3.5% of cardiac arrest cases, 0.1% of patients) were detected after cardiac surgery. Out of 28 cases 7 deaths occurred (25% of cardiac arrest cases, 0.1% of patients). The most prevalent reason for cardiac arrest during post operative phase was massive bleeding (50%) followed by pulseless supra ventricular tachycardia (28.5%). Six patients had some morbidity and the remaining 15 patients recovered. Conclusion: There are often multiple contributing factors to a cardiac arrest under cardiac anesthesia, as much a complete systematic assessment of the patient, equipment, and drugs should be completed. We also found that the diagnosis and management of cardiac arrest in association with cardiac anesthesia differs considerably from that encountered elsewhere. [ABSTRACT FROM AUTHOR]

Cancer continues to be the second leading cause of death worldwide. Discovery of novel therapeutic agents has crucial importance for improvement of our medical management capabilities. Dysregulation of the MET receptor tyrosine kinase pathway plays an important role in cancer progression, making this receptor an attractive molecular target for anticancer drug discovery. In this study, twenty-seven 3,4-dihydropyrimidin-2(1 H)-one C5 amide derivatives were synthesized and their cancer cell growth inhibitory activity was examined against MCF-7, HT-29 and MOLT-4 cells and also NIH/3T3 non-cancer cells by MTT assay. The antiproliferative effect of the most potent derivatives were tested against MET-dependent EBC-1 and MKN-45, lung and gastric cancer cell lines, respectively. MET kinase inhibition was measured by a Homogenous Time Resolved Fluorescence (HTRF) Assay. The influence of the test compounds on cell cycle was examined by RNase/PI flow cytometric assay. A number of compounds exhibited considerable antiproliferative effects against breast and colon cancer and leukemia cell lines, relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at C5 position (15 , 21 , 23 , 31, and 37) showed the highest activities with IC 50 values as low as 10.9 μM. These compounds showed antiproliferative effects also against MET-amplified cells and dose-dependently inhibited MET kinase activity. They also induced G0/G1 cell cycle arrest at lower doses and apoptosis at higher doses. Molecular docking and dynamics simulation studies confirmed the interaction of compound 23 with the active site of the MET receptor. These findings demonstrate that 3,4-dihydropyrimidin-2(1 H)-one analogues may represent promising targeted anticancer agents. [ABSTRACT FROM AUTHOR]

A novel series of 6‐methoxy‐1‐tetralone derivatives bearing N‐aryl pyridinium moiety were designed, synthesized, and evaluated as acetyl and butyrylcholinesterase inhibitors. The designed derivatives inhibited acetylcholinesterase (AChE) with IC50 values of 0.025–23.743 μM and butyrylcholinesterase (BChE) with IC50 values of 0.716–20.588 μM. The synthesized compounds were divided into two series. Derivatives containing N‐benzyl moieties generally were more potent anti‐AChE and anti‐BChE agents than compounds with N‐alkylphthalimide groups. Among them, the compound (E)‐1‐Benzyl‐3‐((6‐methoxy‐1‐oxo‐3,4‐dihydronaphthalen‐2(1H)‐ylidene)methyl)pyridin‐1‐ium bromide (5 a) and compound (E)‐1‐(3‐Chlorobenzyl)‐3‐((6‐methoxy‐1‐oxo‐3,4‐dihydronaphthalen‐2(1H)‐ylidene)methyl)pyridin‐1‐ium bromide (5 d) exhibited significant inhibitory activity against AChE and BChE with IC50 values of 0.025 and 0.716 μM in comparison to donepezil as a reference drug (0.029 and 0.948 μM, respectively). The results of kinetic and molecular modeling studies demonstrated that the synthesized compounds 5 a and 5 d derivatives can act as mixed and dual binding inhibitors, and bind to both CAS and PAS of AChE and BChE enzymes. Among the assessed compounds, the compound 5 a indicated significant neuroprotection against H2O2‐induced cell death in PC12 cells. So, these findings indicate the therapeutic potential of 6‐methoxy‐1‐tetralone derivatives bearing N‐aryl pyridinium moiety derivatives as anti‐AD agents. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and cognitive skills. The current treatment of AD mainly focused on the restoring of ACh levels through acetylcholinesterase (AChE) inhibition. Peptides are a unique class of pharmaceutical compounds that have privilege over small molecules, especially in the realm of protein–protein interactions and G protein-coupled receptor (GPCR) inhibitors. We applied a rational structure-based virtual design approach to discover new peptidic inhibitors of AChE. In this regard, conformational space in the fasciculin II (Fas) and AChE complex was evaluated utilizing MD simulation, principal component analysis and clustering to figure out possible interactions of Fas and AChE. Assessment of Fas–AChE interactions by visual evaluation and alanine scanning led to the design of 10 peptides. The highest scored peptide (p2) was selected and synthesized using SPPS. Based on Ellman's test, the inhibitory activity of p2 against AChE was 51.2 ± 8.1 µM. The kinetics study of the enzyme inhibition in accompany with molecular modeling results revealed that p2 was a mixed-type reversible inhibitor of AChE. The DNRMLRTTRY peptide was considerable inhibitor of AChE. Peptides have the merit of being big enough to inhibit PPI and GPCR class B with a wide binding site. But possible peptidic chemical space is too large to be evaluated by the classical peptide synthesis methods. In the present contribution, we introduced a rational in silico peptide design approach that led to the considerable peptidic inhibitor of AChE. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is one of the most common causes of dementia. Acetylcholinesterase has been considered as the main therapeutic target in the treatment of Alzheimer's disease. Natural products are the richest source of lead compounds for the discovery and development of new drugs. In the present contribution, the hierarchical biology–oriented method was applied to discover the active gradients of F. pseudalliacea root as AChE inhibitors. The Kamonolol acetate was extracted and identified from the n-hexane extract of F. pseudalliacea root. The Kamonolol acetate inhibited the AChE with IC50: 63.9 μM. Molecular modeling studies showed that Kamonolol acetate interacted with CAS and PAS of AChE active site. Kinetics in accompany with molecular modeling studies demonstrated that Kamonolol acetate inhibited AChE in the mixed-type model. The results indicated that Kamonolol acetate could be considered as a valuable lead compound in the design of AChE inhibitors. [ABSTRACT FROM AUTHOR]

A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a–e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f–j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6 k–o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99 μM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56 µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Artoflavanocoumarin possesses essential pharmacophoric groups to inhibit BACE1. • Pseudo-axial and equatorial conformations could freely interconvert. • The maximum affinity of Artoflavanocoumarin was to Asp32p-Asp228i protonation state. Abstract Increasing evidence suggests the beneficial impact of flavonoid-rich nutrition on normal cognitive function. It has been revealed that flavonoids can slow neurodegenerative processes in situations such as Alzheimer's disease (AD). The β-secretase (BACE-1) is one of the most studied targets in AD therapy owing to its role in producing Aβ plaques. In fact the unique role of BACE-1 in pathogenesis of neurodegenerative diseases has made it a druggable target to develop anti-AD agents. Taking into account the anti-amyloidogenic and anti-oxidative properties, flavonoids have received considerable attention as lead candidates for anti-AD drug discovery projects. In continuation to our interest toward rational exploration of potential anti-AD agents, it was attempted to conduct a combined structure based in silico study and explore pharmacophore of a flavanocoumarin derivative as BACE-1 Inhibitor. Ab initio studies showed that both pseudo-axial and pseudo-equatorial conformers could convert to each other freely at room temperature. Within this study it was revealed that artoflavanocoumarin possess essential pharmacophoric groups to inhibit BACE-1. Considering four different protonation states of BACE-1 as di-deprotonated, diprotonated, protonated Asp32 and protonated Asp228, it was also found that affinity of artoflavanocoumarin toward different protonation states of BACE-1could be ranked as Asp32p-Asp228i > di-deprotonated ∼ Asp32i-Asp228p >> diprotonated. PMF study on artoflavanocoumarin showed that it could pass 1.8 kcal/mol free energy barrier from water to DPPC lipid bilayer. Moreover the pros and cons of artoflavanocoumarin as a lead compound were elucidated. [ABSTRACT FROM AUTHOR]

Ferula gummosa Boiss., known in Persian as "Baridje," belongs to the Apiaceae family. All parts of this plant, especially the root, contain galbanum. Galbanum, the oleo-gum resin of F. gummosa , is one of the essential traditional herbal medicines in Iran, which is used as a tonic for epilepsy and chorea, memory enhancement, gastrointestinal diseases, and wound healing. We investigated the toxicity, anticonvulsant effects, and molecular modeling of the essential oil (EO) distilled from the oleo-gum resin of F. gummosa. Gas chromatography-mass spectrometry was used to identify the EO components. The cytotoxicity of EO on HepG2 cell lines was assessed by the MTT method. Male mice were arranged as follows: negative control groups (sunflower oil (10 ml/kg, i.p.) or saline (10 ml/kg, p.o.)), EO groups (0.5, 1, 1.5, and 2.5 ml/kg, p.o.), and positive control groups (ethosuximide (150 mg/kg, p.o.) or diazepam (1.0 or 2 mg/kg, i.p.)). The motor coordination and neurotoxicity of EO were studied using the rota-rod test. Open-field, novel object recognition, and passive avoidance learning tests were used to investigate the effect of EO on locomotor activity and memory function. An acute pentylenetetrazole-induced seizure model was utilized to evaluate the anticonvulsant properties of the EO. The interaction of the EO main components with the GABA A receptor was investigated by coarse-grained molecular dynamics simulations. β-pinene, sabinene, α-pinene, and ρ-cymene were the main components of EO. The IC 50 of the EO at 24, 48, and 72 h was found to be 59.90, 12.96, and 3.93 μl/ml, respectively. No adverse effects were observed in memory, motor coordination, and locomotor activity in mice treated with EO. Administration of EO (1, 1.5, and 2.5 ml/kg) improved survival rates in mice receiving pentylenetetrazole (PTZ; to induce an epileptic seizure). Sabinene was able to bind to the binding site of benzodiazepines at the GABA A receptor. Acute treatment with the EO of F. gummosa caused antiepileptic effects and could effectively increase the survival rate in PTZ-treated mice with no significant toxicity. [Display omitted] • Ferula gummosa Boiss. can be used as supplement therapy in epilepsy treatment. [ABSTRACT FROM AUTHOR]

Monoamine oxidases (MAOs) are amine oxidoreductase falvoenzymes that belong to the integral proteins of the outer mitochondrial membrane. MAO exists in two distinct isoforms; MAO-A and MAO-B. Inhibition of MAO-A and MAO-B is important for developing antidepressant and antiparkinson agents, respectively. In the light of the above explanations, detailed structure binding relationship studies on the intermolecular binding components of MAO-B complexes may unravel the way toward developing novel anti-Parkinson agents. In the present contribution, intermolecular binding pattern for a series of experimentally validated 3-arylcoumarin MAO-B inhibitors ( 1- 9) have been elucidated via molecular docking and density functional theory (DFT) calculations. Intermolecular binding energy components could not be analyzed by docking and due to this limitation, quantum mechanical (QM) calculations including functional B3LYP in association with split valence basis set (Def2-SVP) were applied to estimate the ligand-residue binding energies in the MAO-B active site. Moreover; results were interpreted in terms of calculated polarization effects that were induced by individual amino acids of the MAO-B active site. The results of the present study provide an approach to pharmacophore-based modification within the 3-arylcoumarin scaffold for potent MAO-B inhibitors. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/ AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR inhibitor/drug design. In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach. Molecular docking studies were performed via advanced AutoDock4.2 software. Ensemble docking of Amprenavir into the active site of various conformations of HIV-1 PR predicted different interaction modes/ energies. Analysis of binding factors in terms of docking false negatives/positives revealed a determinant role of enzyme conformational variation in prediction of optimum induced fit (PDB ID: 1HPV). The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents. Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed. [ABSTRACT FROM AUTHOR]

Beta-site amyloid precursor protein cleaving enzyme (BACE-1) is a well-known therapeutic target for Alzheimer disease (AD) due to its characteristic role in the pathogenesis of AD. Numerous researches have been focused on the design and development of potent peptidic and non-peptidic BACE-1 inhibitors. In the present contribution, a series of experimentally validated biflavonoid BACE-1 inhibitors ( 1- 21) were subjected to our structure-based molecular modeling studies. Binding modes were elucidated through molecular docking in the active site of the enzyme. Relatively good correlations between the theoretical and experimental binding affinities could be achieved ( R = 0.61). Analysis of intermolecular binding energy components was performed via functional B3LYP in association with split-valence basis set using polarization functions (Def2-SVP), and structure-binding relationships were further elucidated through ligand-residue binding energies. Since little studies have been performed on the modeling and structure activity/binding relationships of biflavonoid structures as BACE-1 inhibitors, the results of this study may be useful in further extending the scope of biflavonoid structures as potential anti-Alzheimer scaffolds. [ABSTRACT FROM AUTHOR]

Virtual bioactive molecular design is an important part of modern drug discovery projects. In this regard, molecular docking may be looked upon as a well established in silico approach in structure-based hit/lead development. Stereoelectronic complementary fit of a bioactive ligand with its receptor may be predicted by molecular docking. Generally docking simulations are compromised of two principal steps; search algorithm and a scoring function. Search algorithms explore the ligand-receptor configurational space while scoring functions apply molecular mechanic force fields to estimate the free binding energies of various ligand-enzyme poses. In the present contribution, a new probability factor (PF) was proposed that could successfully enhance the predictability of AutoDock4.2 scoring function with regard to FRET-based BACE-1 inhibitory activities of some organic small molecules. BACE-1 or beta site amyloid precursor protein cleaving enzyme is a major therapeutic target for Alzheimer disease due to its determinant role in pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Life expectancy is growing especially in developed countries. In this regard, aging-associated diseases such as Alzheimer's disease (AD) are more common. Multi interconnected pathological factors involved in AD demand multi-target therapeutics. AChE, as a well-known target in AD, decreases the acetylcholine (ACh) in cholinergic synapse and, besides, increases the rate of amyloid-beta (Aβ) aggregation. To block the destructive effects of AChE on cholinergic neurons in AD, we designed a peptidic inhibitor of the peripheral anionic site (PAS). The PAS plays a crucial role to attract and direct the ACh to the enzyme active site and increase the rate of Aβ aggregation by changing the folding state. We utilized the template-based approach in combination with molecular docking, molecular dynamic simulation, and data mining to design a peptide library. Scoring was performed according to binding energy and the interaction profile of AChE inhibitors. The best candidate (p8, RMLRTTRY) was synthesized using solid-phase peptide synthesis, purified by RP-HPLC, and identified by ESI–MS. The inhibitory effect of p8 on AChE was 102.2 ± 15.2 μM. The kinetic and molecular modeling studies indicated the mixed inhibition mechanism for p8. The Arg residues in p8 had an essential role in binding to PAS. [ABSTRACT FROM AUTHOR]

The volatile constituents in the essential oil of I E. bornmuelleri i were investigated by GC/Mass and GC/FID (Table 1). According to the result of GC and GC/mass analysis of the essential oil, 35 compounds were identified, constituting 95.9% of the total essential oil. Among the major essential oil constituents, spathulenol and -bisabolol were reported in other species of I Eryngium i as major compounds, and this result can be used in the chemotaxonomy study of I Eryngium i genus [[5]]. [Extracted from the article]

• In silico approaches applied to design peptidic inhibitors of AChE. • Fragment-based peptide design approach was more efficient than template-based design. • WY dipeptide prevents cognitive impairment and was main component of the p2 peptide (WTWYGYWVW) The prevalence of Alzheimer's disease (AD) has become a substantial global concern. Approved AChE inhibitors have been used for symptomatic treatment of AD. Binding of amyloid β (Aβ) to the peripheral anionic site of AChE facilitates the formation of Aβ plaques. Blocking this proposed protein–protein interaction by inhibition of the peripheral anionic site of AChE, in addition to increasing the level of ACh, reduces the Aβ aggregation and might qualify to slow down the progression of disease besides the palliative treatment. Targeting protein–protein interactions consider as one of the most challenging issues in the realm of drug design in which peptides have potentials to excel in. In the present study, we applied two virtual fragment-based and template-based approaches to design peptidic inhibitors of the PAS of AChE. Based on the in silico studies, high scored peptides p2 (WTWYGYWVW) and p10 (NHRMLTRRY) obtained from fragment-based and template-based design respectively. Regarding in vitro results, p2 (IC 50 = 16 ± 3.2 μM) and p10 (IC 50 = 23.6 ± 4.9 μM) showed significant AChE inhibitory effects. The molecular mechanism of inhibition studied by Lineweaver-Burk plots was mixed inhibition for both peptides. The in vitro results conformed to the in silico results and showed that both peptides occupied the CAS and PAS of AChE. The comparison of two peptide-design approaches revealed that the fragment-based design had more chemical diversity and showed priority to the template-based design. According to the obtained results, peptidic inhibitors of AChE designed by the proposed fragment-based approach might be more efficient in comparison to traditional approaches. [ABSTRACT FROM AUTHOR]

Deoxyribonucleic acid (DNA) is an important molecular target for anti-cancer agents due to its involvement in gene expression and protein synthesis which are fundamental steps in cell division and growth. A number of antineoplastic agents interfere with DNA and hence disturb the cell cycle. Compounds including planar aromatic rings are privileged scaffolds in binding to DNA. This characteristic is mainly arisen from the fact that such structural feature may be appropriate to insert between the base pairs of the DNA double helix and produce relatively stable non-covalent complexes. Besides p-p stacking interactions, binding to the DNA molecule might be intensified through H-bond interactions of heterocyclic rings. In the present contribution, a series of experimentally validated cytotoxic indeno[1,2-b]quinoline-9,11-diones (1-12) and their aromatized analogues (13-21) developed in our group were subjected to docking and molecular dynamics simulations to elucidate their most probable binding modes with DNA. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is a toxic chemical agent that belongs to a class of vesicant compounds. In the 1980s it was used by the Iraqi army against Iranian forces. Sulfur mustard severely irritates the skin, eyes and lungs. The highest side effects seen in patients affected by this gas are pulmonary complications including different types of lung diseases such as bronchiolitis. It has also led to a certain type of chronic obstructive pulmonary disease called mustard lung. Similar extra-pulmonary, molecular and hormonal effects can be observed in these patients and patients with chronic obstructive pulmonary disease. Here cardiovascular complications may be one of the most dangerous visible effects. And atherosclerosis is probable following the direct effects or consequential long-term effects of SM. The development of atherosclerosis in these patients is associated with an increased risk of cardiovascular and coronary artery disease. Coronary artery bypass grafting surgery is the treatment of coronary artery disease. Doing this surgery by bypass pump has its own morbidity and due to local and systemic inflammation changes in patients with SM pulmonary disorders it may have more side effects. Therefore, detailed knowledge of inflammatory diseases as well as the serum level or even the local lung fluid of the inflammatory factors in these patients before surgery are needed so that it would be possible to reduce the rate of morbidity and mortality by normalizing the inflammatory conditions of the patients before cardiac surgery. [ABSTRACT FROM AUTHOR]

Purpose: In this work, gold nanoparticles (GNPs) were embedded in the MAGIC-f polymer gel irradiated with the 192Ir brachytherapy sources. Material and methods: At the first plexiglas phantom was made as the human pelvis. The GNPs were synthesized with 15 nm in diameter and 0.1 mM (0.0197 mg/ml) in concentration by using a chemical reduction method. Then, the MAGIC-f gel was synthesized. The fabricated gel was poured into the tubes located at the prostate (with and without the GNPs) locations of the phantom. The phantom was irradiated with 192Ir brachytherapy sources for prostate cancer. After 24 hours, the irradiated gels was read by using Siemens 1.5 Tesla MRI scanner. Following the brachytherapy practices, the absolute doses at the reference points and isodose curves were extracted and compared by experimental measurements and Monte Carlo (MC) simulations. Results: The mean absorbed doses in the presence of the GNPs in prostate were 14% higher than the corresponding values without the GNPs in the brachytherapy. The gamma index analysis (between gel and MC) using 7%/7 mm was also applied to the data and a high pass rate achieved (91.7% and 86.4% for analysis with/without GNPs, respectively). Conclusions: The real three-dimensional analysis shows the comparison of the dose-volume histograms measured for planning volumes and the expected one from the MC calculation. The results indicate that the polymer gel dosimetry method, which developed and used in this study, could be recommended as a reliable method for investigating the dose enhancement factor of GNPs in brachytherapy. [ABSTRACT FROM AUTHOR]