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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6

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Department: search.filters.department.Department of Chemical and Biological EngineeringSubject: search.filters.subject.Biology

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    PublicationOpen Access
    In silico drug repositioning against human NRP1 to block SARS-CoV-2 host entry
    (TÜBİTAK, 2021) Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Gül, Şeref; Researcher; Graduate School of Sciences and Engineering
    Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here we took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARSCoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr(297), Trp(301), and Tyr(353) amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.
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    PublicationOpen Access
    HMI-PRED 2.0: a biologist-oriented web application for prediction of host-microbe protein-protein interaction by interface mimicry
    (Oxford University Press (OUP), 2022) Lim, H., Tsai, C.J.; Nussinov, R.; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; College of Engineering; 26605; 8745
    HMI-PRED 2.0 is a publicly available web service for the prediction of host-microbe protein-protein interaction by interface mimicry that is intended to be used without extensive computational experience. A microbial protein structure is screened against a database covering the entire available structural space of complexes of known human proteins.
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    PublicationOpen Access
    Human CRY1 variants associate with attention deficit/hyperactivity disorder
    (American Society for Clinical Investigation (ASCI), 2020) Onat, O. Emre; Kars, M. Ece; Bilguvar, Kaya; Wu, Yiming; Özhan, Ayşe; Trusso, M. Allegra; Goracci, Arianna; Fallerini, Chiara; Renieri, Alessandra; Casanova, Jean Laurent; Itan, Yuval; Atbaşoğlu, Cem E.; Saka, Meram C.; Özçelik, Tayfun; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Aydın, Cihan; Başak, Ayşe Nazlı; Kavaklı, İbrahim Halil; Researcher; Researcher; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; 214696; 1512; 40319
    Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.