Publications by authors named "Sahand Golestanian"

5 Publications

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Tetracyclines as a potential antiviral therapy against Crimean Congo hemorrhagic fever virus: Docking and molecular dynamic studies.

Comput Biol Chem 2017 Oct 1;70:1-6. Epub 2017 Jul 1.

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

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is one of the deadliest human diseases with mortality rate near 50%. Special attention should be paid to this virus since there is no approved treatment for it. On the other hand, the recent outbreak of Ebola virus which is a member of hemorrhagic fever viruses shows this group of viruses can be extremely dangerous. Previous studies have indicated that nucleoprotein of CCHFV, a pivotal protein in virus replication, is an appropriate target for antiviral drug development. The aim of this study is finding inhibitor(s) of this protein. Herein, a virtual screening procedure employing docking followed by molecular dynamic was used to identify small molecule inhibitors of the nucleoprotein from FDA-approved drugs. Regarding CCHFV, using in-silico method is a safe way to achieve its inhibitor(s) since this virus is categorized as a World Health Organization (WHO) biosafety level 4 pathogen and therefore investigation in general laboratories is restricted. In conclusion, considering docking and molecular dynamic results alongside with bioavailability of FDA-approved drugs, doxycycline and minocycline are proposed as potential inhibitors of CCHFV nucleoprotein. There is hope, this study encourage other research groups for in-vitro and in-vivo studies about the efficacy of those two medicines in CCHFV treatment.
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http://dx.doi.org/10.1016/j.compbiolchem.2017.06.003DOI Listing
October 2017

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

Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay.

Life Sci 2016 Jan 30;145:240-6. Epub 2015 Dec 30.

Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. Electronic address:

Aims: The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers.

Main Methods: Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds.

Key Findings: Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162μM for Mdm2 and 18 to 233μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2.

Significance: Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.
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http://dx.doi.org/10.1016/j.lfs.2015.12.047DOI Listing
January 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 β-boswellic acid derivatives.

Daru 2013 Jan 2;21(1). Epub 2013 Jan 2.

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

Unlabelled:

Background And The Purpose Of The Study: Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative.

Methods: 4 pentacyclic triterpenoid acids were isolated from Boswellia carterii and identified by NMR and Mass spectroscopic analysis (compounds 1, 3-O-acetyl-9,11-dehydro-β-boswellic acid; 2, 3-O-acetyl-11-hydroxy-β-boswellic acid; 3. 3-O- acetyl-11-keto-β-boswellic acid and 4, 11-keto-β-boswellic acid. Their inhibitory activity on Jack bean urease were evaluated. Docking and pharmacophore analysis using AutoDock 4.2 and Ligandscout 3.03 programs were also performed to explain possible mechanism of interaction between isolated compounds and urease enzyme.

Results: It was found that compound 1 has the strongest inhibitory activity against Jack bean urease (IC50 = 6.27 ± 0.03 μM), compared with thiourea as a standard inhibitor (IC50 = 21.1 ± 0.3 μM).

Conclusion: The inhibition potency is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage.
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http://dx.doi.org/10.1186/2008-2231-21-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575251PMC
January 2013