Publications by authors named "Hourieh Kalhor"

8 Publications

  • Page 1 of 1

Novel Small Molecules against Two Binding Sites of Wnt2 Protein as potential Drug Candidates for Colorectal Cancer: A Structure Based Virtual Screening Approach.

Iran J Pharm Res 2020 ;19(2):160-174

Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran.

Wnts are the major ligands responsible for activating Wnt signaling pathway through binding to Frizzled proteins (Fzd) as the receptors. Among these ligands, Wnt2 plays the main role in the tumorigenesis of several human cancers especially colorectal cancer (). Therefore, it can be considered as a potential drug target. The aim of this study was to identify potential drug candidates against two binding sites of Wnt2. Structure-based virtual screening approaches were applied to identify compounds against binding sites of Wnt2 for inhibiting the interaction Wnt2 and Fzd receptors. The best hit compounds from molecular docking of National Cancer Institute diversity set II database were used for structural similarity search on ZINC database, obtaining large hit compounds query to perform a virtual screening and retrieving potential lead compounds. Eight lead compounds were selected while their binding affinity, binding modes interactions, and molecular dynamics simulations studies were assessed. Molecular docking studies showed that eight selected lead compounds can bind to the desired binding sites of Wnt2 in a high affinity manner. Bioavailability analysis of the selected lead compounds indicated that they possessed significant drug like properties. Thus, these lead compounds were considered as potential drug candidates for inhibiting Wnt signaling pathway through combining with the binding sites of Wnt2 and hindering the interaction of Wnt2 and Fzd receptors. Our findings suggest that Wnt2 binding sites may be a useful target for treatment for CRC fueling the future efforts for developing new compounds against Wnt signaling pathway.
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http://dx.doi.org/10.22037/ijpr.2019.15297.13037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667561PMC
January 2020

Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches.

J Biomol Struct Dyn 2020 Sep 24:1-16. Epub 2020 Sep 24.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

Most recently, the new coronavirus (SARS-CoV-2) has been recognized as a pandemic by the World Health Organization (WHO) while this virus shares substantial similarity with SARS-CoV. So far, no definitive vaccine or drug has been developed to cure Covid-19 disease, since many important aspects about Covid-19 such as pathogenesis and proliferation pathways are still unclear. It was proven that human ACE2 is the main receptor for the entry of Covid-19 into lower respiratory tract epithelial cells through interaction with SARS-CoV-2 S protein. Based on this observation, it is expected that the virus infection can be inhibited if protein-protein interaction is prevented. In this study, using structure-based virtual screening of FDA databases, several lead drugs were discovered based on the ACE2-binding pocket of SARS-CoV-2 S protein. Then, binding affinity, binding modes, critical interactions, and pharmaceutical properties of the lead drugs were evaluated. Among the previously approved drugs, Diammonium Glycyrrhizinate, Digitoxin, Ivermectin, Rapamycin, Rifaximin, and Amphotericin B represented the most desirable features, and can be possible candidates for Covid-19 therapies. Furthermore, molecular dynamics (MD) simulation was accomplished for three S protein/drug complexes with the highest binding affinity and best conformation and binding free energies were also computed with the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Results demonstrated the stable binding of these compounds to the S protein; however, in order to confirm the curative effect of these drugs, clinical trials must be done.
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http://dx.doi.org/10.1080/07391102.2020.1824816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576931PMC
September 2020

Effects of tosyl-l-arginine methyl ester (TAME) on the APC/c subunits: An in silico investigation for inhibiting cell cycle.

J Mol Graph Model 2020 06 5;97:107563. Epub 2020 Feb 5.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address:

The anaphase-promoting complex/cyclosome (APC/c) is requisite for controlling mitosis, which is activated by Cdh1 and Cdc20 activators. Dysregulation of APC/c is observed in many cancers and is known as a targeted drug particularly in cancer drug resistance. It was shown that tosyl-l-arginine methyl ester (TAME), via mimicking isoleucine-arginine (IR) tail of co-activators, inhibits APC/c functions. However, structure details and interaction of TAME with APC/c are poorly defined. In the current study, a well-established set of computational methods was used to identify the best binding pocket in order to inhibit APC activity. Therefore, the interaction of IR tail and Cbox of co-activators, as well as TAME as an inhibitor, as an inhibitor, with APC3 and APC8 subunits of APC/c were analyzed, regarding structure, molecular docking, molecular dynamics, and free binding energy. The results indicated that TAME bound to APC3 with a higher binding affinity (∼-7.3 kcal/mol) than APC8 (∼-5.7 kcal/mol). Also, the binding free energy value obtained for the APC3-TAME was -22.25 ± 1.12 kcal/mol. According to binding free energies, van der Waals energy was the major favorable contributor to the ligand binding. These results offer that TAME had more affinity to interact with the APC3 subunit, at the IR binding pocket than the APC8 subunit at the Cbox binding pocket. In conclusion, IR binding pocket can serve as an appropriate potential target for TAME as an inhibitor of APC/c.
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http://dx.doi.org/10.1016/j.jmgm.2020.107563DOI Listing
June 2020

In silico mutagenesis in recombinant human keratinocyte growth factor: Improvement of stability and activity in addition to decrement immunogenicity.

J Mol Graph Model 2020 06 28;97:107551. Epub 2020 Jan 28.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address:

The recombinant human keratinocyte growth factor (rhKGF) is clinically applied to decrease the incidence and duration of cancer therapeutic agents. Particularly, it is extensively used for oral mucositis after chemotherapy-induced damage of different human cancers. However, the usage of rhKGF in treatment is limited owing to its short half-life, poor stability, immunogenicity, tendency to aggregate, and side effects. Therefore, there is a need to enhance the stability and to reduce immunogenicity of rhKGF for therapeutic applications. In this study, the stability, activity, and immunogenicity of rhKGF were improved using computational methods. The several mutations were generated based on sequence alignment, amino acids physic-chemical properties, and the structure simulation. The 3D structure of rhKGF and proposed mutants were predicted by Modeller v9.15 program, and then were evaluated using PROSESS, PROCHECK, and ProSA web tools. Afterwards, the effect of these mutants on rhKGF structure, stability, activity, and its interaction with fibroblast growth factor receptor2-IIb (FGFR2-IIb) was analyzed through utilizing GROMACS molecular dynamics simulations and docking tools, respectively. Also, binding free energies were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. We found that F63Y, R121K, and combine1 (K38R, F63Y, K72E, N105S) mutants lead to reduction of the number of T-cell epitopes. However, all of the selected mutants, except for R121K, could considerably increase stability and affinity of the rhKGF to FGFR2-IIb, in silico. In conclusion, this study, for the first time, offered that the combine1 and F63Y mutants could highly improve the stability and activity of rhKGF and even reduce immunogenicity without having any significant effect on the biological functions of rhKGF.
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http://dx.doi.org/10.1016/j.jmgm.2020.107551DOI Listing
June 2020

Identification of candidate genes and miRNAs for sensitizing resistant colorectal cancer cells to oxaliplatin and irinotecan.

Cancer Chemother Pharmacol 2020 01 28;85(1):153-171. Epub 2019 Nov 28.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

Drug resistance to irinotecan and oxaliplatin, two widely used chemotherapeutic, has become a common problem in cancerous patients. Despite numerous valuable studies, distinct molecular mechanisms involved in the acquisition of resistance to these anti-cancer drugs have remained a challenge. In this study, we studied the possible resistance mechanisms to irinotecan and oxaliplatin in three CRC cell lines (HCT116, HT29, and LoVo) via integration of microarray data with gene regulatory networks. After determination of hub genes, corresponding miRNAs were predicted using several databases and used in construction and subsequent analysis of miRNA-gene networks. Following to preparation of chemo-resistance CRC cells, a standard real-time PCR was conducted for validation of in silico findings. Topological and functional enrichment analyses of the resulted networks introduced several previously reported drug-resistance genes as well as novel biomarkers as hub genes which seem to be crucial in resistance of colon cancer cells to irinotecan and oxaliplatin. Furthermore, results of the functional annotation revealed the essential role of different signaling pathways like metabolic pathways in drug resistance of CRC cell lines to these drugs. A part of in silico findings was also validated in vitro using oxaliplatin-resistant cell lines. While FOXC1 and NFIC were upregulated in cell lines which were resistant to oxaliplatin, silencing FOXC1 decreased the resistance of SW480 cell line to oxaliplatin. In conclusion, our comparative in silico and in vitro study introduces several novel genes and miRNAs as the resistance-mediators which can be used for sensitizing resistant CRC cells to oxaliplatin and irinotecan.
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http://dx.doi.org/10.1007/s00280-019-03975-3DOI Listing
January 2020

Identification of new DNA gyrase inhibitors based on bioactive compounds from streptomyces: structure-based virtual screening and molecular dynamics simulations approaches.

J Biomol Struct Dyn 2020 02 27;38(3):791-806. Epub 2019 Mar 27.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

DNA gyrase enzyme has vital role in bacterial survival and can be considered as a potential drug target. Owing to the appearance of resistance to gyrase-targeted drugs, especially fluoroquinolone, screening new compounds which bind more efficiently to the mutant binding pocket is essential. Hence, in this work, using Smina Autodock and through structure-based virtual screening of StreptomeDB, several natural products were discovered based on the SimocyclinoneD8 (SD8) binding pocket of GyrA subunit of DNA gyrase. After evaluation of binding affinity, binding modes, critical interactions and physicochemical and pharmaceutical properties, three lead compounds were selected for further analysis. Afterward 60 ns molecular dynamics simulations were performed and binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area method. Also, interaction of the selected lead compounds with the mutated GyrA protein was evaluated. Results indicated that all of the selected compounds could bind to the both wild-type and mutated GyrA with the binding affinities remarkably higher than SimocyclinoneD8. Interestingly, we noticed that the selected compounds comprised angucycline moiety in their structure which could sufficiently interact with GyrA and block the DNA binding pocket of DNA gyrase, . In conclusion, three DNA gyrase inhibitors were identified successfully which were highly capable of impeding DNA gyrase and can be considered as potential drug candidates for treatment of fluoroquinolone-resistant strains.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1588784DOI Listing
February 2020

Structural and dynamic characterization of human Wnt2-Fzd7 complex using computational approaches.

J Mol Model 2018 Sep 6;24(10):274. Epub 2018 Sep 6.

Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran.

Wnt and Frizzled (Fzd) family members play crucial roles in the self-renewal of tumor-initiating cells. Until now, only a few studies have addressed the distinct mechanism of Wnt-Fzd interactions. In this study, we suggest a possible interaction mode of Wnt2 with the Fzd7 cysteine-rich domain (CRD)-both of which are up-regulated in some types of cancer. A combination of homology modeling, molecular docking and molecular dynamics (MD) simulations was carried out to study this ligand-receptor complex in great detail. The results demonstrated the unique dynamic behavior of Wnt2 upon binding to Fzd7. Interestingly, the β-strand content of the C-terminal binding site of Wnt2 was obviously reduced when bound to Fzd7 CRD. Moreover, the N-terminal and C-terminal binding sites of Wnt2 appeared to interact with the C-terminal and N-terminal binding sites of Fzd7, respectively. Calculation of the binding energies uncovered the pivotal role of electrostatic and hydrophobic interactions in the binding of Wnt2 to Fzd7 CRD. In conclusion, this study provides valuable insights into the mechanism of the Wnt2-Fzd7 CRD interaction for application in colorectal cancer prevention programs. Graphical abstract Flowchart representation of different steps used in this study.
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http://dx.doi.org/10.1007/s00894-018-3788-3DOI Listing
September 2018

In silico enhancement of the stability and activity of keratinocyte growth factor.

J Theor Biol 2017 04 16;418:111-121. Epub 2017 Jan 16.

Molecular Medicine Department, Biotechnology Research Center., Pasteur Institute of Iran, Iran. Electronic address:

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, has been implicated in some biological processes such as cell proliferation, development and differentiation. High mitogenic activity of this protein has made it very suitable for repairing radiation-and chemotherapy-induced damages. Palifermin, which has been developed from human KGF, is clinically applied to reduce the incidence and duration of cancer therapeutic agents. However, the activity of Palifermin is limited during treatment due to its poor stability. In this study, we have improved the stability and activity of recombinant human KGF (Palifermin) using a computational mutagenesis approach. According to the KGF multiple sequence alignment among different species as well as literature-based information, we have generated several mutations using PyMOL program and evaluated their effects on the stability and activity of KGF in silico. In order to preserve the KGF activity, we did not change the predicted functional residues. Prior to mutagenesis, the 3D structure of rhKGF was predicted by Modeller v9.15 program and quantitative evaluation of predicted models were carried out using VADAR and PROSESS servers. The stability and activity of rhKGF mutants were analyzed using GROMACS molecular dynamics (MD) simulations and docking tools, respectively. The results showed that N159S (N105S in rhKGF sequence) and I172V (I118V in rhKGF) substitutions caused an increased stability and affinity of the rhKGF to Fibroblast growth factor receptor 2 (FGFR2). We will evaluate the effects of favorable mutations on the rhKGF stability and activity in vitro.
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http://dx.doi.org/10.1016/j.jtbi.2017.01.009DOI Listing
April 2017