فهرست مطالب nima razzaghi asl

P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent membrane efflux pump for protecting cells against xenobiotic compounds. Unfortunately, overexpressed P-gp in neoplastic cells prevents cell entry of numerous chemotherapeutic agents leading to multidrug resistance (MDR). MDR cells may be re-sensitized to chemotherapeutic drugs via P-gp inhibition/modulation. Side effects of synthetic P-gp inhibitors encouraged the development of natural products.

Experimental approach: 

Molecular docking and density functional theory (DFT) calculations were used as fast and accurate computational methods to explore a structure binding relationship of some dietary phytochemicals inside distinctive P-gp binding sites (modulatory/inhibitory). For this purpose, top-scored docked conformations were subjected to per-residue energy decomposition analysis in the B3LYP level of theory with a 6-31g (d, p) basis set by Gaussian98 package.

Consecutive application of computational techniques revealed binding modes/affinities of nutritive phytochemicals within dominant binding sites of P-gp. Blind docking scores for best-ranked compounds were superior to verapamil and rhodamine-123. Pairwise amino acid decomposition of superior docked conformations revealed Tyr303 as an important P-gp binding residue. DFT-based induced polarization analysis revealed major electrostatic fluctuations at the atomistic level and confirmed larger effects for amino acids with energy-favored binding interactions. Conformational analysis exhibited that auraptene and 7,4',7'',4'''-tetra-O-methylamentoflavone might not necessarily interact to P-gp binding sites through minimum energy conformations.

Conclusion and implications: 

Although there are still many hurdles to overcome, obtained results may propose a few nutritive phytochemicals as potential P-gp binding agents. Moreover; top-scored derivatives may have the chance to exhibit tumor chemo-sensitizing effects.

A few 2-aryl-1H-phenanthro [9,10-d] imidazoles were synthesized and assessed for their cytotoxicity against MCF-7, HepG2, and AGS cell lines using MTT assay. Cellular assessments showed that phenanthroimidazoles were extremely potent cytotoxic agents (sub-nanomolar IC50s). Maximum effect was recorded for para-N-phenyl acetamide containing derivative against AGS cells (IC50 0.07 nM). It was also revealed that phenanthroimidazole derivatives showed better cytotoxicity against MCF-7 and AGS cells when compared to HepG2 cells. Minimum cytotoxicity was reported for para-methylphenyl derivatives within HepG2 cancer cells (IC50 7608.07 nM). Structure-activity relationship studies indicated that incorporation of nitrogen/oxygen-containing polar groups such as N-acetyl or nitro into para/meta positions of phenyl ring significantly enhanced the cytotoxicity against AGS cells. A similar trend was observed in meta-nitro derivatives vs MCF-7 cells. It was revealed that even the least potent compound exhibited cytotoxic activity in the range of low micromolar IC50. Results of this study proposed 2-aryl-1H-phenanthro [9,10-d] imidazoles as privileged structures for further in vivo studies.

Human papillomavirus (HPV) is known as the main reason for cervical cancer. According to carcinogenic risk, HPV can be located into two classes, counting the low-risk virus, which is the main cause of genital warts and low-grade cervical epithelial lesions. HPV-16 is one of the high-risk HPV subtypes in the spectrum of cervical diseases.

Experimental approach: 

The PubChem database was screened in order to identify potential anti-HPV hits followed by ADMET predictions. Then, molecular docking was performed to improve the accuracy of  screening and also to find the details of the interactions of the hit compounds with the active site. Finally, molecular dynamic (MD) simulations and free binding energy on top-ranked structures CID_73212812, CID_91059286, CID_69838075, cidofovir, and jaceosidin were carried out with protein to compute the interaction energies and stability of the top-ranked compounds at the active site.

Based on molecular docking studies, three compounds including CID_73212812, CID_91059286, and CID_69838075 exhibited the best results among compounds against the E6 protein of HPV-16. Furthermore, RMSD, RMSF, hydrogen binds, Rg, and energy analysis during MD simulation certainly indicated the stable binding of selected compounds with E6 protein of HPV-16 active site.

Conclusion and implications:

 Docking and MD results revealed that hydrophobic contacts and optimum hydrogen bonds were determinant factors in the interactions of hits and the E6 protein of HPV-16. In addition, the binding energy portions exposed that Van der Waals and non-polar interactions were fundamental factors in the molecule binding.

< p>Computer-aided drug design provides broad structural modifications to evolving bioactive molecules without an immediate requirement to observe synthetic restraints or tedious protocols. Subsequently, the most promising guidelines with regard to synthetic and biological resources may be focused on upcoming steps. Molecular docking is common in-silico drug design techniques since it predicts ligand-receptor interaction modes and associated binding affinities. Current docking simulations suffer serious constraints in estimating accurate ligand-receptor binding affinities despite several advantages and historical results. Response surface method (RSM) is an efficient statistical approach for modeling and optimization of various pharmaceutical systems. With the aim of unveiling the full potential of RSM in optimizing molecular docking simulations, this study particularly focused on binding affinity prediction of citalopram-serotonin transporter (SERT) and donepezil-acetyl cholinesterase (AChE) complexes. For this purpose, Box-Behnken design of experiments (DOE) was used to develop a trial matrix for simultaneous variations of AutoDock4.2 driven binding affinity data with selected factor levels. Responses of all docking trials were considered as estimated protein inhibition constants with regard to validated data for each drug. The output matrix was subjected to statistical analysis and constructing polynomial quadratic models. Numerical optimization steps to attain ideal docking accuracies revealed that more accurate results might be envisaged through the best combination of factor levels and considering factor interactions. Results of the current study indicated that the application of RSM in molecular docking simulations might lead to optimized docking protocols with more stable estimates of ligand-target interactions and hence better correlation of in-silico in-vitro data.

 Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents. 

 In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines.

 Among the assessed compounds, one of the DHPMT derivatives (compound 5</strong>: </strong>4-(3-fluorophenyl)-6-methyl-N</em>-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 </sub>9.9 µM; MCF-7, IC50 </sub>15.2 µM; and Hep-G2, IC50 </sub>40.5 µM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs).

 DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta </em>position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells. 

The prevalence of leishmaniasis is reported in more than 98 countries and Iran is one of the endemic areas. There is no vaccine for this disease and few effective drugs are available to treat it. Moreover, drug resistance to the disease is increasing. During the past decade, several in vitro and in vivo studies have been performed on dihydropyrimidine derivatives as antileishmanial agents.

In the present project, a few 6-methyl-4-aryl-N-aryl dihydropyrimidinone/thiones (A7-A11) and N-heteroaryl-3-(para-methoxy benzyl) amino but-enamides (A1-A6) were synthesized, structurally characterized, and finally subjected to in vitro anti-leishmanial effect against Leishmania major promastigotes.

Results of the study showed that compound A10, 4-(3-chlorophenyl)-6-methyl-N-phenyl2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, exhibited superior anti-leishmanial effect with IC50 value of 52.67 µg/mL (more active than standard drug Glucantim® with IC50 71000 ± 390 µg/mL).

It was demonstrated that some dihydropyrimidine thiones were able to inhibit Leishmania major promastigotes. Structure-activity relationship evaluations indicated that more electron-poor rings such as isoxazole afforded higher activity within A1-A6 series and in these derivatives, N-benzothiazole rings reinforced anti-leishmanial activity concerning thiazole. It was also observed that higher anti-parasite activities of A10 and A11 concerning A7-A9 might be related to the incorporation of the sulfur atom into C2 position, replacement of N-thiazole carboxamide by N-phenyl carboxamide on C5 position of dihydropyrimidine ring, and also replacement of para with meta-substituted phenyls within C4 of dihydropyrimidine ring. The results may help unveil new 4-aryl-5-carboxamide dihydropyrimidines as potential anti-leishmanial agents and their further structural modification toward more potent derivatives.

Cancer prevalence has increased in the last century posing psychological, social, and economic consequences. Chemotherapy uses chemical molecules to control cancer. New studies have shown that dihydropyrimidinethione (DHPMT) derivatives have the potential of being developed into anticancer agents.

New derivatives of DHPMTs and a few acyclic bioisosters were synthesized via Biginelli reaction and assessed for their toxicity against gastric (AGS) and breast cancer (MCF-7) cell lines through MTT method.

Chemical structures of all synthesized N-heteroaryl enamino amides and DHPMTs were confirmed by spectroscopic methods. Result of biological assessment exhibited that none of the tested agents was more cytotoxic than cis-platin against AGS and MCF-7 cell lines and compound 2b was the most cytotoxic agent against AGS (IC50</sub> 41.10 µM) and MCF-7 (IC50</sub> 75.69 µM). Cytotoxic data were mostly correlated with the number of H-bond donors within gastric and breast cancer cells. 

It was realized that DHPMTs were able to inhibit the growth of cancer cells much better than acyclic enamino amides and moreover; N-(4-methylbenzothiazol-2-yl) DHPMT derivative (2b) supposed possible interaction with a poor electron site of target due to the lipophilic nature of benzothiazole ring and also less electron rich nature than isoxazole. Similar scenario was observed with acyclic enamino amides in which incorporation of sulfur and nitrogen containing heterocycles doubled the cytotoxic effects. Results of the present contribution might assist in extending the scope of DHPMTs as privileged medicinal scaffolds. 

Heracleum is one of the greatest genera of the Umbelliferae family that has more than 120 species. This genus is represented by 109 species in Asia. Common names for the genus or its species include hogweed and cow parsnip. This paper discusses the phytochemistry, ethnopharmacological use and pharmaceutics of Heracleum species. Many kinds of metabolites have been isolated and identified, that furanocoumarins are among the significant ones. Modern pharmacological studies demonstrated that Heracleum and its active compounds have extensive biological activity, particularly in anticonvulsant, anti-inflammatory, antifungal, anticancer, anti-psoriatric, anti-vitiligo and antioxidant activities. In clinical test, Heracleum has successfully been utilized to treat psoriasis, vitiligo, carminative, stomachs, pain killer and anticonvulsant.

the interaction of albumin- the most important plasma protein- with various drugs leads to variations in the pharmacokinetics of drugs. Since interaction of different pharmaceuticals with albumin is determinant in the estimation of dose and prediction of drug-drug and drug-food interferences, studying the binding ability of different drugs with albumin is an active area of research.
Docking studies were performed by Lamarckian Genetic Algorithm of AutoDock 4.2 program. The three-dimensional structures of albumin were obtained from Brookhaven protein data bank (2BXD & 2BXF; www.rcsb.org). Pre-processing of molecules was done using AM1 method and AutoDock Tools 1.5.4 software. AM1 optimization method was performed using Polak-Ribiere (conjugate gradient) algorithm with termination condition as RMS gradient of 0.1 Kcal/Å mol. Schematic representation of drug-albumin complexes were obtained by Ligplot.
Oxiconazole and fenticonazole were top-ranked drugs in binding to site 1 (subdomain IIA) and 2 (subdomain IIIA) of albumin, respectively (∆Gb -9.01 and -9.89 kcal.mol-1). Leu238 and Ala291 were the key residues of site 1 due to hydrophobic contacts with all of the antifungals, while Ile388, Asn391 and Leu430 were the key residues of site 2. A few structure binding relationship rules could be extracted from the binding pattern of antifungal drugs.
It was found that antifungal agents might have higher affinity toward site 2 of albumin rather than site 1. Estimated high albumin affinities of antifungals provided the possibility of drug-drug or drug-food interactions. It seemed that hydrophobic contacts were more significant in binding antifungals to albumin.

In this study, Copper oxide as a good and inexpensive adsorbent has been introduced and used for the removal of erythrosine and red carmoisine dyes from several water solutions successfully. The effect of various parameters such as pH, dye concentration, amount of adsorbent, contact time and temperature on removal processing was investigated. Adsorption isothermal data could be interpreted by the Langmuir and  Freundlich, isotherm models.

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.

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 (BACE-1). It is a membrane associated protein and is one of the main enzymes responsible for amyloid β (Aβ) production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the attention of scientists, because peptidic inhibitors have many pharmacokinetic problems. In the present study, several small molecule BACE-1 inhibitors were extracted from Brookhaven Protein Databank (PDB) and subjected to dissection analysis to achieve constructing fragments. Atom type, hybridization, and bond order were considered for generated constitutional fragments (simplified structures). AutoDock version 4.2 was applied to dock various chemical fragments into BACE-1 active site. The benefits of such studies have been well revealed in previous reports. On the basis of obtained binding affinities, fragment-based ligand efficiency (LE) indices were estimated. These theoretical binding efficiencies were applied to further elucidate the key structural features of BACE-1 inhibitors. Typical results of the study were elucidated and we suggested the ways these findings might be beneficial to guide rational bioactive molecular developments. Our study confirmed that the evaluation of ligand-receptor interactions in terms of ligand efficiency indices (binding energy per atom and pKi per MW) could be a helpful strategy in structure-based drug discovery (SBDD) strategies.

In this study , Copper oxide as a good and inexpensive adsorbent has been introduced and used for the removal of erythrosine and red carmoisine dyes from several water solutions successfully. The effect of various parameters such as pH, dye concentration, amount of adsorbent, contact time and temperature on removal processing was investigated. Adsorption isothermal data could be interpreted by the Langmuir and Freundlich, isotherm models.

In this study , Copper oxide as a good and inexpensive adsorbent has been introduced and used for the removal of erythrosine and red carmoisine dyes from several water solutions successfully. The effect of various parameters such as pH, dye concentration, amount of adsorbent, contact time and temperature on removal processing was investigated. Adsorption isothermal data could be interpreted by the Langmuir and  Freundlich, isotherm models.

Low-cost grapefruit peel (Agricultural Waste) was used for removal of reactive blue19 dye from aqueous solutions. The process was studied as a function of contact time, initial dye concentration and pH. Adsorption process was attained to the equilibrium within 45 min for initial dye concentrations of 50, 75, and 100 mg L-1. An acidic medium was the optimum condition for adsorption of dye at room temperature. The maximum dye removal of 83.56 % could be achieved at initial pH 2 using adsorbent dosage of 0.5 mg in 150 ml (50 mg L-1 dye concentration) and agitation rate of 180 rpm. The adsorption capacity was found to be about 12.534 mg g-1. The isotherm data could be well described via Langmuir equation with the correlation coefficient of 0.986 in dye concentration range of 50-100 mg L-1 at 25 ◦C. Kinetic studies revealed that the experimental data correlated well with pseudo second-order model possessing regression coefficient of R2 ≥ 0.999. Scanning Electron Micrographs provided a supporting evidence for efficient dye sorption onto grapefruit peel.

In this work, a new spectrophotometric method for the determination of trace amount of Cobalt (ІІ) ionwas investigated and the stability constant of the related complex was evaluated 2.174 × 104. In the Cobalt(ІІ)-piroxicam complex, the maximum absorbance wavelength is 570 nm and the linearity of calibrationcurve was investigated (5-10 ppm). The relative standard deviation for seven replicate experiments is0.5292 percent. The accuracy is 0.15 percent and limit of detection is 1.19 ppm. The analytical sensitivityallows us to detect the concentration difference of 0.06 ppm with reliable level of confidence. The ligand tometal ratio was determined (1:1) by the continuous variation method. The above spectrophotometricmethod was optimized in terms of pH, temperature, time, ligand concentration and ionic strength. Thismethod is tolerant against several external matters, which means high selectivity.