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Article ; Online: Hybrid

Sahin, Kader / Orhan, Muge Didem / Avsar, Timucin / Durdagi, Serdar

ACS pharmacology & translational science

2021 Volume 4, Issue 3, Page(s) 1111–1123

Abstract: B-Cell lymphoma 2 (BCL-2) regulates cell death in humans. In this study, combined ... ...

Abstract	B-Cell lymphoma 2 (BCL-2) regulates cell death in humans. In this study, combined multiscale
Language	English
Publishing date	2021-04-15
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.0c00210
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Anti-SARS-CoV-2 and cytotoxic activity of two marine alkaloids from green alga

Erol, Ebru / Orhan, Muge Didem / Avsar, Timucin / Akdemir, Atilla / Okudan, Emine Sukran / Alim Toraman, Gulbahar Ozge / Topcu, Gulacti

RSC advances

2022 Volume 12, Issue 46, Page(s) 29983–29990

Abstract: ... Caulerpa ... ...

Abstract	Caulerpa cylindracea
Language	English
Publishing date	2022-10-19
Publishing country	England
Document type	Journal Article
ISSN	2046-2069
ISSN (online)	2046-2069
DOI	10.1039/d2ra03358e
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Article: Integrating Ligand and Target-Driven Based Virtual Screening Approaches With

Tutumlu, Gurbet / Dogan, Berna / Avsar, Timucin / Orhan, Muge Didem / Calis, Seyma / Durdagi, Serdar

Frontiers in chemistry

2020 Volume 8, Page(s) 167

Abstract: Antiapoptotic members ... ...

Abstract	Antiapoptotic members of
Language	English
Publishing date	2020-04-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2020.00167
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Article ; Online: An Integrated in silico Approach and in vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies.

Kanan, Duaa / Kanan, Tarek / Dogan, Berna / Orhan, Muge Didem / Avsar, Timucin / Durdagi, Serdar

ChemMedChem

2020 Volume 16, Issue 3, Page(s) 555–567

Abstract: The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous ... ...

Abstract	The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Molecular Dynamics Simulation ; Molecular Structure ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors ; Ubiquitin-Specific Peptidase 7/metabolism
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Small Molecule Libraries ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
Language	English
Publishing date	2020-11-12
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202000675
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Article ; Online: Proposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studies.

Aydin, Gulsah / Paksoy, Maide Nur / Orhan, Müge Didem / Avsar, Timucin / Yurtsever, Mine / Durdagi, Serdar

Chemical biology & drug design

2020 Volume 96, Issue 1, Page(s) 684–700

Abstract: The mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53-suppressing mechanisms involve the ... ...

Abstract	The mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53-suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high-throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all-atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds (E1-E11) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds (E1, E2, E5, E6, E9, and E11) in breast cancer cell lines and six compounds (E1, E2, E5, E6, E8, and E10) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis.
MeSH term(s)	Animals ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/adverse effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacokinetics ; High-Throughput Screening Assays/methods ; Humans ; Mice ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Protein Conformation ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/metabolism ; Quantitative Structure-Activity Relationship ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacokinetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Small Molecule Libraries ; Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2020-07-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2216600-2
ISSN	1747-0285 ; 1747-0277
ISSN (online)	1747-0285
ISSN	1747-0277
DOI	10.1111/cbdd.13694
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Article ; Online: Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2: A Combined in silico and in vitro Study.

Durdagi, Serdar / Orhan, Muge Didem / Aksoydan, Busecan / Calis, Seyma / Dogan, Berna / Sahin, Kader / Shahraki, Aida / Iyison, Necla Birgül / Avsar, Timucin

Molecular informatics

2021 Volume 41, Issue 2, Page(s) e2100062

Abstract: In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual ...

Abstract	In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Antiviral Agents/pharmacology ; Cefotiam/pharmacology ; Coronavirus 3C Proteases/antagonists & inhibitors ; Drug Evaluation, Preclinical ; Drug Repositioning ; Drugs, Investigational/pharmacology ; Humans ; Molecular Docking Simulation ; Ritonavir/pharmacology ; SARS-CoV-2/drug effects ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Drugs, Investigational ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Cefotiam (91W6Z2N718) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Ritonavir (O3J8G9O825)
Language	English
Publishing date	2021-09-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537668-8
ISSN	1868-1751 ; 1868-1743
ISSN (online)	1868-1751
ISSN	1868-1743
DOI	10.1002/minf.202100062
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Article ; Online: The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies.

Durdagi, Serdar / Avsar, Timucin / Orhan, Muge Didem / Serhatli, Muge / Balcioglu, Bertan Koray / Ozturk, Hasan Umit / Kayabolen, Alisan / Cetin, Yuksel / Aydinlik, Seyma / Bagci-Onder, Tugba / Tekin, Saban / Demirci, Hasan / Guzel, Mustafa / Akdemir, Atilla / Calis, Seyma / Oktay, Lalehan / Tolu, Ilayda / Butun, Yasar Enes / Erdemoglu, Ece /

Olkan, Alpsu / Tokay, Nurettin / Işık, Şeyma / Ozcan, Aysenur / Acar, Elif / Buyukkilic, Sehriban / Yumak, Yesim

Molecular therapy : the journal of the American Society of Gene Therapy

2021 Volume 30, Issue 2, Page(s) 963–974

Abstract: Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the ... ...

Abstract	Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).
MeSH term(s)	A549 Cells ; Acetates/chemistry ; Acetates/pharmacology ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Cell Survival/drug effects ; Chlorocebus aethiops ; Cyclopropanes/chemistry ; Cyclopropanes/pharmacology ; Drug Repositioning ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Docking Simulation ; Molecular Structure ; Neutralization Tests ; Protein Conformation ; Quinolines/chemistry ; Quinolines/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/metabolism ; Sulfides/chemistry ; Sulfides/pharmacology ; Vero Cells ; Virus Internalization/drug effects
Chemical Substances	Acetates ; Cyclopropanes ; Quinolines ; Sulfides ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; montelukast (MHM278SD3E)
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2021.10.014
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Article ; Online: The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

Olkan, Alpsu / Tokay, Nurettin / Işık, Şeyma / Ozcan, Aysenur / Acar, Elif / Buyukkilic, Sehriban / Yumak, Yesim

bioRxiv

Abstract: Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel ...

Abstract	Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of Montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the Fluorescent Resonance Energy Transfer (FRET)-based main protease enzyme inhibition assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T / hACE2, and virus neutralization assay using xCELLigence MP real time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of the Montelukast both on virus entry into the host cell (Spike/ACE2) and on the main protease enzyme inhibition. The virus neutralization assay results showed that while no cytotoxicity of the Montelukast was observed at 12 micro-molar concentration, the cell index time 50 (CIT50) value was delayed for 12 hours. Moreover, it was also shown that Favipiravir, a well-known antiviral used in COVID-19 therapy, should be used by 16-fold higher concentrations than Montelukast in order to have the same effect of Montelukast. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and if its effect is proven in clinical phase studies, it should be used against COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-12-27
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.12.26.424423
Database	COVID19

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Article ; Online: The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

Olkan, Alpsu / Tokay, Nurettin / Isik, Seyma / Ozcan, Aysenur / Acar, Elif / Buyukkilic, Sehriban / Yumak, Yesim

bioRxiv

Abstract	Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of Montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the Fluorescent Resonance Energy Transfer (FRET)-based main protease enzyme inhibition assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T / hACE2, and virus neutralization assay using xCELLigence MP real time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of the Montelukast both on virus entry into the host cell (Spike/ACE2) and on the main protease enzyme inhibition. The virus neutralization assay results showed that while no cytotoxicity of the Montelukast was observed at 12 micro-molar concentration, the cell index time 50 (CIT50) value was delayed for 12 hours. Moreover, it was also shown that Favipiravir, a well-known antiviral used in COVID-19 therapy, should be used by 16-fold higher concentrations than Montelukast in order to have the same effect of Montelukast. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and if its effect is proven in clinical phase studies, it should be used against COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-12-27
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.12.26.424423
Database	COVID19

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