Publications by authors named "Kowsar Bagherzadeh"

15 Publications

  • Page 1 of 1

In silico maturation of affinity and selectivity of DNA aptamers against aflatoxin B for biosensor development.

Anal Chim Acta 2020 Apr 24;1105:178-186. Epub 2020 Jan 24.

Department of Plant Protection, College of Agricultural Sciences & Engineering, University of Tehran, Karaj, 31587-77871, Iran. Electronic address:

A high affinity and selectivity DNA aptamer for aflatoxin B (AFB) was designed through Genetic Algorithm (GA) based in silico maturation (ISM) strategy. The sequence of a known AFB aptamer (Patent: PCT/CA2010/001292, Apt1) applied as a probe in many aptasensors was modified using seven GA rounds to generate an initial library and three different generations of ss DNA oligonucleotides as new candidate aptamers. Molecular docking methodology was used to screen and analyze the best aptamer-AFB complexes. Also, a new pipeline was proposed to faithfully predict the tertiary structure of all single stranded DNA sequences. By the second generation, aptamer Apt1 sequence was optimized in the local search space and five aptamers including F20, g12, C52, C32 and H1 were identified as the best aptamers for AFB. The selected aptamers were applied as probes in an unmodified gold nanoparticles-based aptasensor to evaluate their binding affinity to AFB and their selectivity against other mycotoxins (aflatoxins B, G, G, M, ochratoxin A and zearalenone). In addition, a novel direct fluorescent anisotropy aptamer assay was developed to confirm the binding interaction of the selected aptamers over AFB The ISM allowed the identification of an aptamer, F20, with up to 9.4 and 2 fold improvement in affinity and selectivity compared to the parent aptamer, respectively.
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http://dx.doi.org/10.1016/j.aca.2020.01.045DOI Listing
April 2020

Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc Complex: Virtual Screening, Synthesis, and Biochemical Assay.

Interdiscip Sci 2018 Dec 18;10(4):781-791. Epub 2017 Sep 18.

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions. Subsequently, the application of rational filtering procedure over the target database resulted in the elucidation of a novel class of cyt bc complex potent inhibitors with comparable binding energies and biological activities to those of the standard inhibitor, antimycin.
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http://dx.doi.org/10.1007/s12539-017-0241-8DOI Listing
December 2018

Chondrotinase ABC I thermal stability is enhanced by site-directed mutagenesis: a molecular dynamic simulations approach.

J Biomol Struct Dyn 2018 02 1;36(3):679-688. Epub 2017 Mar 1.

b Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Medicinal Chemistry , Tehran University of Medical Sciences , Tehran , Iran.

Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of growth in the adult central nervous system. Use of the enzyme chondroitinase ABC I (ChABC I) as a strategy to reduce CSPG inhibition in experimental models of spinal cord injury has led to observations of its remarkable capacity for repair. More importantly, ChABC therapy has been demonstrated to promote significant recovery of function to spinal injured animals. Despite this incomparable function of ChABC I, its clinical application has been limited because of its thermal instability as reported in the literature. In a recent study by Nazari-Robati et al., thermal stability of ChABC I was improved by protein engineering using site-directed mutagenesis method. Here, in this study, molecular dynamics simulations were used to take a closer look into the phenomenon leading to the experimentally observed thermal stability improvement followed by the corresponding site-directed mutagenesis. We concluded that the mutations induce local flexibility along with a re-conformation into the native structure which consequently increase the protein thermal stability.
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http://dx.doi.org/10.1080/07391102.2017.1294110DOI Listing
February 2018

A comparative study based on docking and molecular dynamics simulations over HDAC-tubulin dual inhibitors.

J Mol Graph Model 2016 11 7;70:170-180. Epub 2016 Oct 7.

Department of Medicinal Chemistry & Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Nowadays the ability to prediction of complex behavior rationally based on the computational approaches has been a successful technique in drug discovery. In the present study interactions of a new series of hybrids, which were made by linking colchicine as a tubulin inhibitor and suberoylanilide hydroxamic acid (SAHA) as a HDAC inhibitor, with HDAC8 and HDAC1 were investigated and compared. This research has been facilitated by the availability of experimental information besides employing docking methodology as well as classical molecular dynamics simulations and binding free energy calculation were performed. The obtained findings indicate different modes of interactions and inhibition strengths of the studied inhibitors for HDAC8 and HDAC1. HDAC8 binding free energies (-34.35 to -26.27kcal/mol) revealed higher binding affinity to HDAC8 compared to HDAC1 (-33.17 to -7.99kcal/mol). The binding energy contribution of each residue with the hybrid compounds 4a-4e within the active site of HDAC1 and HDAC8 was analyzed and the results confirmed the rule of key amino acids in interaction with the hybrid compounds.
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http://dx.doi.org/10.1016/j.jmgm.2016.10.007DOI Listing
November 2016

An investigation on the interaction modes of a single-strand DNA aptamer and RBP4 protein: a molecular dynamic simulations approach.

Org Biomol Chem 2016 Sep 11;14(34):8141-53. Epub 2016 Aug 11.

Laboratory of Microanalysis, Institute of Biochemistry & Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.

Type two diabetes is one of the primary health issues threatening public well-being worldwide. One of the pre-diagnosis biomarkers of this disease, retinol binding protein 4 (RBP4), has been demonstrated to be detected with a 76-mer ssDNA aptamer instead of conventional antibodies. However, there is no structural information on the RBP4 binding aptamer (RBA) and the mechanism of its binding to RBP4 still remains unexplored. The objective of the present study is to achieve a better understanding of specific binding interactions of the target protein (RBP4) and RBA, employing Molecular Dynamics simulations (MDs) to provide detailed information on fluctuations, conformational changes, critical bases and effective forces to develop regulated aptamers to be employed in designing new aptamers for many useful recognition applications. RBA was designed according to its reported base pair sequence and secondary structure. The HADDOCK on line docking program was used to predict a suitable RBP4-RBA mode of interaction to start MDs with. MDs methodology was used to analyze the final complex stability and detect interacting residues. Eventually, we conclude that single strand located bases are the key components that conduct the intercalation phenomenon with big targets rather than those involving loops and folded motifs, to encompass targets and probably inhibit their activity. Also, UV-visible, circular dichroism and fluorescence spectroscopy measurements confirmed the interactions between RBA and RBP4 and RBP4-RBA complex formation.
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http://dx.doi.org/10.1039/c6ob01094fDOI Listing
September 2016

Arylhydrazone derivatives of naproxen as new analgesic and anti-inflammatory agents: Design, synthesis and molecular docking studies.

J Mol Graph Model 2016 06 24;67:127-36. Epub 2016 May 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Electronic address:

A series of new arylidenehydrazone derivatives of naproxen were synthesized and evaluated for their analgesic and anti-inflammatory activities. Some of the synthesized analogues showed comparable activities when compared against naproxen for their analgesic and anti-inflammatory properties. 2-(6-methoxy-2-naphthyl)-N'-[(pyridine-4-yl)methylene]propanoic acid hydrazide 4j was found to be the most active analgesic agent. 2-(6-methoxy-2-naphthyl)-N'-[4-nitrobenzylidene]propanoic acid hydrazide 4g showed highest anti-inflammatory activity in comparison to the naproxen. Molecular modeling study of the synthesized compounds suggested that the designed molecules were well located and bound to the COX-1 and COX-2 active sites. Compound 4g showed the highest selectivity for COX-2 (RCOX-2/COX-1=1.94) and higher affinity rather than naproxen in COX-2 active site (RCOX-2/naproxen=1.28). Moreover, the structural analyses confirmed that the E-ap rotamer is the preferred structure for the arylidenehydrazone derivatives.
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http://dx.doi.org/10.1016/j.jmgm.2016.05.009DOI Listing
June 2016

Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein.

Comb Chem High Throughput Screen 2016 ;19(3):228-37

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase with a key role in cell proliferation, death and differentiation. Mutations in EGFR, including substitution of Thr790 by methionine and Leu858 by arginine (T790M/L858R), lead to a lung cancer that is resistant against first generation inhibitors. In fact, second generation inhibitors were developed, but they proved to have had severe side effects because of the significant potency to suppress the wild type protein just as much. To resolve the problem, a step-by-step rational virtual screening was employed over almost sixty million compounds of PubChem Compound Database to filter out selective inhibitor(s) of T790M/L858R subtype. Consequently, the compound CID 133077 was observed, an active metabolite of Axitirome and also a cholesterol lowering prodrug. Selecting this compound can be explained by the oxamic acid part of molecule. Hence, administration of Axitirome or other compounds which contain oxamic acid is suggested in cases with EGFR T790M/L858R drug resistance.
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http://dx.doi.org/10.2174/1386207319666160115132121DOI Listing
December 2016

Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays.

J Chem Inf Model 2015 Dec 2;55(12):2596-610. Epub 2015 Dec 2.

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences , Tehran, 14155-6451, Iran.

Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well-known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design.
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http://dx.doi.org/10.1021/acs.jcim.5b00336DOI Listing
December 2015

Urease Inhibitory Activities of some Commonly Consumed Herbal Medicines.

Iran J Pharm Res 2015 ;14(3):943-7

Department of Medicinal Chemistry, Faculty of Pharmacy and Medicinal Plants Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Urease enzyme has a crucial role in the persistent habitation of Helicobacter pylori (H. pylori) that induces gastrointestinal diseases, in particular gastritis, duodenal, peptic ulcer, and gastric cancer. Plants have long been utilized as the biggest source of substances with medicinal properties from natural origin and therefore result in less toxicity and adverse side effects upon usage. 15 medicinal plant extracts were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 80% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Three plant extracts including Ginkgo biloba, Rhus coriaria, and Matricaria inodora were found to be the most effective ones with IC50 values of 36.17, 80.29, and 100.6 μg/mL, respectively.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518124PMC
September 2015

Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer's disease.

J Biomol Struct Dyn 2016 8;34(4):855-69. Epub 2015 Jul 8.

a Molecular Simulation Research Laboratory, Department of Chemistry , Iran University of Science & Technology , Tehran , Iran.

The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short-term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine, and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase and butylcholinesterase) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analog of B7T, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations have been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have raised the potency of the analog in comparison with the parent compound to design more potent multi target ligands to heal Alzheimer's disease.
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http://dx.doi.org/10.1080/07391102.2015.1057526DOI Listing
December 2016

Screening of 20 commonly used Iranian traditional medicinal plants against urease.

Iran J Pharm Res 2014 ;13(Suppl):195-8

Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Infection with Helicobacter pyloriis the most common cause of stomach and duodenal ulcers. About more than 80 % of people are infected with H. pylori in developing countries. H. pylori uses urease enzyme product "ammonia" in order to neutralize and protect itself from the stomach acidic condition and urease enzyme activity has been shown to be essential to the colonization of H. pylori. Inhibitory activity of 20 traditional medicinal plants were examined and evaluated against Jack bean urease activity by Berthelot reaction to obtains natural sources of urease inhibitors. Each herb was extracted using 80% aqueous methanol, then tested its IC50 value was determined. Eight of the whole 20 studied plants crude extracts were found the most effective with IC50 values of less than 100 μg/mL including Laurus nobilis, Zingiber officinale, Nigella sativa, Angelica archangelica, Acorus calamus, Allium sativum,Curcuma longa, and Citrus aurantium extracts, from which most potent urease inhibitory was observed for Zingiber officinale, Laurus nobilis, and Nigella sativa with IC50 values of 48.54, 48.69 and 59.10 μg/mL, respectively.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977070PMC
April 2014

A new insight into mushroom tyrosinase inhibitors: docking, pharmacophore-based virtual screening, and molecular modeling studies.

J Biomol Struct Dyn 2015 6;33(3):487-501. Epub 2014 Mar 6.

a Department of Medicinal Chemistry, Faculty of Pharmacy and Medicinal Plants Research Center , Tehran University of Medical Sciences , Tehran , Iran.

Tyrosinase, a widely spread enzyme in micro-organisms, animals, and plants, participates in two rate-limiting steps in melanin formation pathway which is responsible for skin protection against UV lights' harm whose functional deficiency result in serious dermatological diseases. This enzyme seems to be responsible for neuromelanin formation in human brain as well. In plants, the enzyme leads the browning pathway which is commonly observed in injured tissues that is economically very unfavorable. Among different types of tyrosinase, mushroom tyrosinase has the highest homology with the mammalian tyrosinase and the only commercial tyrosinase available. In this study, ligand-based pharmacophore drug discovery method was applied to rapidly identify mushroom tyrosinase enzyme inhibitors using virtual screening. The model pharmacophore of essential interactions was developed and refined studying already experimentally discovered potent inhibitors employing Docking analysis methodology. After pharmacophore virtual screening and binding modes prediction, 14 compounds from ZINC database were identified as potent inhibitors of mushroom tyrosinase which were classified into five groups according to their chemical structures. The inhibition behavior of the discovered compounds was further studied through Classical Molecular Dynamic Simulations and the conformational changes induced by the presence of the studied ligands were discussed and compared to those of the substrate, tyrosine. According to the obtained results, five novel leads are introduced to be further optimized or directly used as potent inhibitors of mushroom tyrosinase.
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http://dx.doi.org/10.1080/07391102.2014.893203DOI Listing
January 2016

Large scale screening of commonly used Iranian traditional medicinal plants against urease activity.

Daru 2012 Oct 31;20(1):72. Epub 2012 Oct 31.

School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran.

Background And Purpose Of The Study: H. pylori infection is an important etiologic impetus usually leading to gastric disease and urease enzyme is the most crucial role is to protect the bacteria in the acidic environment of the stomach. Then urease inhibitors would increase sensitivity of the bacteria in acidic medium.

Methods: 137 Iranian traditional medicinal plants were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 50% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined.

Results: 37 plants out of the 137 crude extracts revealed strong urease inhibitory activity (more than 70% inhibition against urease activity at 10 mg/ml concentration). Nine of the whole studied plants crude extracts were found as the most effective with IC50 values less than 500 μg/ml including; Rheum ribes, Sambucus ebulus, Pistachia lentiscus, Myrtus communis, Areca catechu, Citrus aurantifolia, Myristica fragrans, Cinnamomum zeylanicum and Nicotiana tabacum.

Conclusions: The most potent urease inhibitory was observed for Sambucus ebulus and Rheum ribes extracts with IC50 values of 57 and 92 μg/ml, respectively.
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http://dx.doi.org/10.1186/2008-2231-20-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556030PMC
October 2012

Association of saliva fluoride level and socioeconomic factors with dental caries in 3-6 years old children in tehran-iran.

Iran J Pharm Res 2011 ;10(1):159-66

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, 14155-6451, Tehran, Iran.

Previous studies have indicated that there may be a relationship between the salivary fluoride concentrations and dental caries while the emphasis was on dental caries in permanent teeth. The aim of this study was to assess the prevalence of dental caries and its predictors in 3-6 year-old children in Tehran, Iran. The other objective of this investigation was to clarify a relationship between salivary fluoride levels of the studied children and their socioeconomic situations. The study population consisted of 205 children aged 3-6 years living in Tehran. Each child was examined for dental caries (decayed missing filled teeth (DMFT)) and unstimulated whole mixed saliva was collected 2 h post-prandial. All of the saliva samples were analyzed for fluoride concentration using an ion-specific electrode. The children were then grouped according to their DMFT, salivary fluoride levels (ppm) and socioeconomic factors (parent's education and occupation) that resulted in a statistically significant relationship. The children with (DMFT < 1) were shown to have a significantly higher salivary fluoride level (p < 0.001) than prone children caries (DMFT > 1). The obtained results indicated that the caries prevalence among 3-6 year-old children in Tehran - the capital of the Islamic republic of Iran - is as low compared with those, living in developed countries.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869581PMC
December 2013

A theoretical study on interactions between mitoxantrone as an anticancer drug and DNA: application in drug design.

Chem Biol Drug Des 2008 May 29;71(5):474-482. Epub 2008 Mar 29.

Institute of Petroleum Engineering, Faculty of Engineering, University of Tehran, Tehran, IranCenter of Excellence in Electrochemistry, Faculty of Chemistry, University of Tehran, P. O. Box 14155-6455, Tehran, IranMedical Nanotechnology Research Centre, Medical Sciences/University of Tehran, Tehran, P.O. Box 14155-6451, Iran.

This research is an effort to further understand the physicochemical interaction between the novel drug, mitoxantrone (MTX) and its biologic receptor, DNA. The ultimate goal is to design drugs that interact more with DNA. Understanding the physicochemical properties of the drug as well as the mechanism by which it interacts with DNA, it should ultimately allow the rational design of novel anti-cancer or anti-viral drugs. Molecular modelling on the complex formed between MTX and DNA presented that this complex was indeed fully capable of participating in the formation of a stable intercalation site. Furthermore, the molecular geometries of MTX and the DNA bases (adenine, guanine, cytosine and thymine) were optimized with the aid of the B3LYP/6-31G* method. The properties of the isolated intercalator and its stacking interactions with the adenine...thymine (AT) and guanine...cytosine (GC) nucleic acid base pairs were studied with the DFTB method (density functional tight-binding), an approximate version of the DFT method, that was extended to cover the London dispersion energy. The B3LYP/6-31G* stabilization energies of the intercalator...base pair complexes were found 10.06 kcal/mol and 21.64 kcal/mol for AT...MTX and GC...MTX, respectively. It was concluded that the dispersion energy and the electrostatic interaction contributed to the stability of the intercalator.DNA base pair complexes. The results concluded from the comparison of the DFTB method and the Hartree-fock method point out that these methods show close results and support each other.
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http://dx.doi.org/10.1111/j.1747-0285.2008.00653.xDOI Listing
May 2008