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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials(Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.Publication Open Access The photolyase/cryptochrome family of proteins as DNA repair enzymes and transcriptional repressors(Wiley, 2017) Aydın, Cihan; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Kavaklı, İbrahim Halil; Barış, İbrahim; Tardu, Mehmet; Gül, Şeref; Öner, Haşimcan; Bulut, Selma; Yarparvar, Darya; Ustaoğlu, Pınar; Teaching Faculty; PhD Student; Researcher; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; College of Engineering; College of Sciences; 40319; 111629; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/ALight is a very important environmental factor that governs many cellular responses in organisms. As a consequence, organisms possess different kinds of light-sensing photoreceptors to regulate their physiological variables and adapt to a given habitat. The cryptochrome/photolyase family (CPF) includes photoreceptors that perform different functions in different organisms. Photolyases repair ultraviolet-induced DNA damage by a process known as photoreactivation using photons absorbed from the blue end of the light spectrum. On the other hand, cryptochromes act as blue light circadian photoreceptors in plants and Drosophila to regulate growth and development. In mammals, cryptochromes have light-independent functions and are very important transcriptional regulators that act at the molecular level as negative transcriptional regulators of the circadian clock. In this review, we highlight current knowledge concerning the structural and functional relationships of CPF members.Publication Open Access Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing(Elsevier, 2021) Durdağı, Serdar; Doğan, Berna; Avşar, Timuçin; Erol, İsmail; Çalış, Şeyma; Orhan, Müge D.; Aksoydan, Busecan; Şahin, Kader; Oktay, Lalehan; Tolu, İlayda; Olkan, Alpsu; Erdemoğlu, Ece; Yefanov, Oleksandr M.; Dao, E. Han; Hayes, Brandon; Liang, Mengning; Seaberg, Matthew H.; Hunter, Mark S.; Batyuk, Alex; Mariani, Valerio; Su, Zhen; Poitevin, Frederic; Yoon, Chun Hong; Kupitz, Christopher; Sierra, Raymond G.; Snell, Edward H.; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; N/A; Demirci, Hasan; Dağ, Çağdaş; Büyükdağ, Cengizhan; Ertem, Fatma Betül; Yıldırım, Günseli; Destan, Ebru; Güven, Ömür; Ayan, Esra; Yüksel, Büşra; Göcenler, Oktay; Can, Özgür; Özabrahamyan, Serena; Tanısalı, Gökhan; Faculty Member; Faculty Member; Undergraduate Student; PhD Student; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Koç Üniversitesi İş Bankası Enfeksiyon Hastalıkları Uygulama ve Araştırma Merkezi (EHAM) / Koç University İşbank Center for Infectious Diseases (KU-IS CID); College of Sciences; Graduate School of Sciences and Engineering; School of Nursing; 307350; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/AThe COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.