Researcher:
Aydın, Cihan

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Researcher

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Cihan

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Aydın

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Aydın, Cihan

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2015 - 20205

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Researcher Of Publications: search.filters.isAuthorOfPublication.163c85f4-e458-48e7-8804-5ad4b4d67f1c

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    Structural and thermodynamic effects of macrocyclization in HCV NS3/4A inhibitor MK-5172
    (Amer Chemical Soc, 2016) Soumana, Djade I.; Yilmaz, Nese Kurt; Prachanronarong, Kristina L.; Ali, Akbar; Schiffer, Celia A.; Department of Chemical and Biological Engineering; Aydın, Cihan; Researcher; Department of Chemical and Biological Engineering; College of Engineering; 214696
    Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively low susceptibility to resistance. MK-5172 has a P2-P4 macrocycle and a unique binding mode among current protease inhibitors where the P2 quinoxaline packs against the catalytic residues H57 and D81. However, the effect of macrocyclization on this binding mode is not clear, as is the relation between macrocyclization, thermodynamic stabilization, and susceptibility to the resistance mutation A156T. We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics, and experimental binding thermodynamics to the parent compound. We find that the "unique" binding mode of MK-5172 is conserved even when the P2-P4 macrocycle is removed or replaced with a P1-P3 macrocycle. While beneficial to decreasing the entropic penalty associated with binding, the constraint exerted by the P2-P4 macrocycle prevents efficient rearrangement to accommodate the A156T mutation, a deficit alleviated in the linear and P1-P3 analogs. Design of macrocyclic inhibitors against NS3/4A needs to achieve the best balance between exerting optimal conformational constraint for enhancing potency, fitting within the substrate envelope and allowing adaptability to be robust against resistance mutations.
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    Simultaneously targeting the NS3 protease and helicase activities for more effective hepatitis C virus therapy
    (American Chemical Society, 2015) Ndjomou, Jean; Corby, M. Josie; Sweeney, Noreena L.; Hanson, Alicia M.; Ali, Akbar; Schiffer, Celia A.; Li, Kelin; Frankowski, Kevin J.; Schoenen, Frank J.; Frick, David N.; Department of Chemical and Biological Engineering; Aydın, Cihan; Researcher; Department of Chemical and Biological Engineering; College of Engineering; 214696
    This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevir-resistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety of wildtype and mutant NS3 proteins suggested that HPI forms a bridge between the NS3 RNA-binding cleft and an allosteric site previously shown to bind other protease inhibitors. In most combinations, the antiviral effect of HPI was additive with telaprevir and boceprevir, minor synergy was observed with danoprevir, and modest synergy was observed with grazoprevir. © 2015 American Chemical Society.
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    Squamous cell carcinoma metastasis in pleural and pericardial effusions
    (Springer, 2019) Sunnetcioglu, E.; Hurdogan, O.; Yilmazbayhan, D.; Ozluk, Y.; Department of Chemical and Biological Engineering; N/A; Aydın, Cihan; Fırat, Pınar Arıkan; Researcher; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; School of Medicine; Koç University Hospital; 214696; 207545
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    Oncogenic K-Ras4B dimerization enhances downstream mitogen-activated protein kinase signaling
    (Academic Press Ltd- Elsevier Science Ltd, 2020) Jang, Hyunbum; Tsai, Chung-Jung; Nussinov, Ruth; N/A; N/A; N/A; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; N/A; Department of Chemical and Biological Engineering; Muratçıoğlu, Serena; Aydın, Cihan; Odabaşı, Ezgi; Karalar, Elif Nur Fırat; Kavaklı, İbrahim Halil; Özdemir, E. Sıla; Keskin, Özlem; Gürsoy, Attila; PhD Student; Researcher; Other; Faculty Member; Faculty Member; PhD Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; N/A; N/A; College of Sciences; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; Department of Computer Engineering; N/A; 214696; 26605; 8745; 206349; 40319; 26605; 8745
    Ras recruits and activates effectors that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, Raf's activation requires dimerization, which can be facilitated by Ras dimerization. Previously, we showed that active K-Ras4B dimerizes in silico and in vitro through two major interfaces: (i) beta-interface, mapped to Switch I and effector-binding regions, (ii) alpha-interface at the allosteric lobe. Here, we chose constitutively active K-Ras4B as our control and two double mutants (K101D and R102E; and R41E and K42D) in the alpha- and beta-interfaces. Two of the mutations are from The Cancer Genome Atlas (TCGA) and the Catalogue of Somatic Mutations In Cancer (COSMIC) data sets. R41 and R102 are found in several adenocarcinomas in Ras isoforms. We performed site-directed mutagenesis, cellular localization experiments, and molecular dynamics (MD) simulations to assess the impact of the mutations on K-Ras4B dimerization and function. alpha-interface K101D/R102E double mutations reduced dimerization but only slightly reduced downstream phosphorylated extracellular signal-regulated kinase (ERK) (pERK) levels. While beta-interface R41E/K42D double mutations did not interfere with dimerization, they almost completely blocked KRas4B-mediated ERK phosphorylation. Both double mutations increased downstream phosphorylated Akt (pAkt) levels in cells. Changes in pERK and pAkt levels altered ERK- and Akt-regulated gene expressions, such as EGR1, JUN, and BCL2L11. These results underscore the role of the alpha-interface in K-Ras4B homodimerization and the beta-surface in effector binding. MD simulations highlight that the membrane and hypervariable region (HVR) interact with both alpha- and beta-interfaces of K-Ras4B mutants, respectively, inhibiting homodimerization and probably effector binding. Mutations at both interfaces interfered with mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase signaling but in different forms and extents. We conclude that dimerization is not necessary but enhances downstream MAPK signaling.
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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; Gül, Şeref; Aydın, Cihan; Başak, Ayşe Nazlı; Kavaklı, İbrahim Halil; Researcher; Researcher; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; 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.