Doktora Tezleri

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12469/7776

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Augmented Virtual Crossmatch for Donor-Induced Antibody Prediction by Using High Resolution Human Leukocyte Antigen Typing and Human Leukocyte Antigen Epitope Mapping for Better Donor Match
(Kadir Has Üniversitesi, 2023) Karadeniz, Sedat Tanju; Yelekçi, Kemal
The Human Leukocyte Antigen (HLA) disparity between donors and recipients is the primary driver of Donor Specific Antibodies (DSA) formation and graft rejection after transplantation. We aimed to predict the DSA by finding the HLA antigen mismatches, searching the eplets of antigens that bind to the recipient's anti-HLA antibodies, calculating the number of shared eplets between the mismatched donor HLA antigens and the recipient's pre-transplantation anti-HLA antibody-bound antigens. We have used recipient-donor HLA Typing results and the recipient's pre-transplantation and post-transplantation anti-HLA antibody detection results by Luminex single antigen bead (Luminex-SAB) assay as retrospective data for calculation in five steps. We have compared the HLA Typing results to find the mismatched antigens in the first step and searched the relevant eplets for the recipient's pre-transplantation anti-HLA antibodies in the second step. Then we calculated the shared eplets between the donor's mismatched HLA antigens and the recipient's pre-transplantation anti-HLA antibodies to find the highest number of shares, then listed the most shared anti-HLA antibodies as the most probable DSA in the fourth step. Then, we confirmed the possible epitope's peptide AA (amino acid) sequences with the IEDB Bepipred-1.0 Antibody Epitope Prediction method using the donor's HLA antigen AA sequence.
Identification of Distinct Communication Networks in Human ?2 Adrenergic Receptor Via Molecular Dynamics Simulation
(Kadir Has Üniversitesi, 2020) Erdoğan, Nuray Söğünmez
G-protein-bağlı reseptörler (GPCR), hücre dışı ligand bağlanma işlemini hücre içi tepkilere dönüştürerek çok çeşitli insan fizyolojik fonksiyonlarına aracılık eden ve yedi transmembran (TM) yapısından oluşan proteinlerdir. Karşılıklı sinyal aktarımı, ancak iki uzak bölge arasında allosterik iletişimle oluşur. Hem inaktif hem de aktif kristal yapıların mevcut olduğu bir arketipik GPCR olan insan β2-adrenerjik reseptörüne (β2AR) odaklandık. β2AR 'ın farklı konformasyonlarının yörüngelerini oluşturmak için moleküler dinamik (MD) simülasyonları gerçekleştirildi. Burada, β2AR'a ait orijinal inaktif durum (Faz I), çok inaktif durum (Faz II), ara durum ve G-proteine bağlı aktif durumun yörüngelerini kullanarak potansiyel iletişim ağlarını araştırdık. Bu nedenle, bu tezde nedenselliğe bağlı potansiyel allosterik etkileşim ve bilgi aktarımını ortaya çıkarmak için proteindeki Cα dalgalanmaları ve omurga/yan zincir dihedral açı rotasyonları üzerinde hem korelasyon hem de entropi bazlı olasılıksal yaklaşımlar kullanılmıştır. Serbest ICL3 içeren yapılarda bilgi akışı yönü hücre içinden hücre dışına doğru iken, ICL3'ün hareketinin kısıtlandığı yapılarda bu akış yönünün tam tersine olduğu görüldü. Ayrıca, esnek alanlarda lokalize olmuş amino asitler genellikle polar özelliklere sahip olup iletişime büyük katkıda bulunmuşlardır. aktif-Gp için bağımsız iki çalışma, ICL3'ün z-yönünde hareketi ile birbirinden ayrılmış ve burada G proteini etkisinden dolayı iletişim ve polarite gücünün azaldığı saptanmıştır. Son olarak, mutlak Cα dalgalanma değerleri ve sterik engeller farklı dihedral açılarının oluşmasına neden olabildiğinden, Cα dalgalanmaları ve dihedral açıların ortak hareketi gözlemlenmemiştir. Bu nedenle de dihedral verilerde çoğunlukla ilmik alanlarının ortaya çıktığı görüntülenmiştir. Bu sonuçlar β2AR 'daki allosterik iletişimi açıklamak için yapı temelli bir mekanizma sağlamakta ve dahası rasyonel ilaç tasarımı ve protein mühendisliği gibi uygulamalar için bir temel oluşturmaktadır.
In silico designing of isoform-selective inhibitors against class IIA histone deacetylases
(Kadir Has Üniversitesi, 2021) Elmezayen, Ammar Dawoud Ahmed Mahmoud; Yelekçi, Kemal
The fundamental cause of human cancer is strongly influenced by down- or upregulations of epigenetic factors. Upregulated histone deacetylases (HDAC) have been shown to be effectively neutralized by the action of HDACs inhibitors (HDACi). However, cytotoxicity has been reported in normal cells because of non-specificity of several available HDACis that are in clinical use or at different phases of clinical trials. Constant Search for specific HDAC isoform inhibitors is increasingly developing to avoid this side effect. Because of the high amino acid sequence and structural similarity among HDAC enzymes, it is believed to be a challenging task to obtain isoform-selectivity. The essential aim of the present study was to examine the similarity of class IIa HDACs (4, 5, 7, and 9) by aligning their structures and amino acid sequences, active site extraction, and recognition of the key amino acid residues within the catalytic channel. X-ray crystal structure of the human HDAC4 was used as a template for homology modeling of human HDACs 5 and 9. Consequently, isoform-selective inhibitors against class IIa HDACs were identified via structure- and ligand-based drug design. Based on the highest binding affinity and isoform-selectivity, the top-ranked inhibitors were in silico tested for their absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, which were classified as drug-like compounds. Later, molecular dynamics simulation (MD) was carried out for all compound-protein complexes to evaluate the structural stability and the biding mode of the inhibitors, which showed high stability throughout the 100 ns simulation. Free binding energy predictions by MM-PBSA method showed the high binding affinity of the identified compounds towards their respective targets. Hence, these inhibitors could be used as drug candidates or as lead compounds for more in silico or in vitro optimization to design safe isoform-selective HDACs inhibitors.
In Silico Modeling of Dopamine Transporter and Design of Novel Neuroprotective Drugs for Parkinson's Disease
(Kadir Has Üniversitesi, 2017) Dikic, Teodora; Yelekçi, Kemal
Parkinson hastalıgı (PH), substantia nigra (SN) ve corpus striatum (CS) bolgelerinde dopamin ureten noronların kaybedilmesi ile karakterize edilen bir olgudur. Yaygın olarak uygulanan tedavi dopamin noronlarının kaybolmalarının korunması yonunde degilde ortaya cıkan semtopların azaltılmasına yoneliktir. Insan dopamin tranporteri (hDAT) yoluyla spesifik olarak sinir hucresine alınan ve dopaminerjik noronları hedefleyen secici sinir koruyucu (noron protektif) ilaclar gecerli bir strateji olabilir. Tedavide dopaminin hucre dısı biyoaktif mikatını artırabilen dolayısı ile dopaminerjik norotransmisyonun kaybını dengeleyen ve kuvvetlendiren ve sitoplazmada birikerek noroprotektif olarak davranabilen molekuller gerekir. Bu calısmada homoloji modelleme, molekuler doklama ve molekuler dinamik simulasyon metodları kullanılarak substrat ve inhibitorle komplekslenmis hDAT'ın uc boyutlu (3D) yapı modelleri bulunmustur. Gelecekte yapılacak ilac tasarımlarında onemli olan bilesiklerin farklı baglanma kinetiklerini acıklayabilen hDAT'ın acık ve kapalı konformasyonları olusturulmustur. In silico yaklasımla elde edilmis olan yapılar bilesik veri bankası taraması sonucunda bize umit vadeden uc substrat molekulunun tespit edilmesine olanak saglamıstır. Bu substratların in vitro canlı hucre goruntu deneyleriyle hDAT'a dayalı fluoresan substratın hucreye geri girisi (uptake) inhibe etme etkileri de analiz edilmistir. Butun bu sonuclar birlikte degerlendirildiginde calısmamız in silico/in vitro yaklasımılarını birlikte kullanılarak dopaminerjik notron spesifik substratlların seciminde bir ilk model olusturmaktadır.
Citation - WoS: 8
Citation - Scopus: 8
Screening of Novel and Selective Inhibitors for Neuronal Nitric Oxide Synthase (nnos) Via Structure-Based Drug Design Techniques
(Kadir Has Üniversitesi, 2022) boumezber, sarah; Yelekci, Kemal
The overproduction of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS) is the main cause of several neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Multiple Sclerosis (MS). NO is produced in many cell types by three isoforms of NOS (nNOS, iNOS, and eNOS) and has various biological functions, generally, for its significant reactivity with proteins. NOS isoforms share a high sequence and structure similarity, specifically in the active site, which makes the development and design of nNOS inhibitors extremely challenging; mainly, no-selective inhibitors can affect iNOS and eNOS physiological roles. To date, there is no selective inhibitor against nNOS in the market with desirable ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties, and pass the blood-brain barrier (BBB). With improvement of computational drug design techniques and accessibility of the X-ray crystal structures, development of novel drugs became less expensive and faster. Our research benefited from the structure-based drug design approaches to investigate proficient and selective inhibitors against nNOS. After structure-based virtual screening, the selective top-ranked compounds were filtered according to the ADMET prediction; then, the candidates with a high affinity with a suitable ADMET profile were subject to 100 ns molecular dynamics (MD) simulations. The stability through the 100 ns run has been evident for some nominated inhibitors, which are valuable lead compounds that can be optimized to reach the greatest physicochemical properties in addition to the selectivity.
Targeting Cancer Epigenetic Modifiers: the Design of Isoform-Selective Histone Deacetylase Inhibitors
(Kadir Has Üniversitesi, 2018) Uba, Abdullahi İbrahim; Yelekçi, Kemal
Epigenetic alterations are believed to be the common hallmark of human cancers. Histone deacetylase (HDAC) inhibitors have proven to be effective in cancer cases where HDACs are up-regulated. However lack of selectivity of many of the HDAC inhibitors in clinical use and those at various stages of preclinical and clinical trials causes toxicity to the normal cells. it is believed that the continuous identification of isoform-selective HDAC inhibitors can eliminate this adverse effect — a task that remains particularly challenging due to the high sequence and structural conservations around the active site of HDAC isoforms. The original contribution of this study was analyzing the similarity among class i HDACs (1 2 3 and 8) and class iib HDACs (6 and 10) by sequence and structural alignments catalytic channel extraction and identification of catalytically essential amino acid residues. in addition homology model of human HDAC10 was built using a recently-released X-ray crystal structure of Danio rerio (zebrafish) HDAC10 as a template. Using these data isoform-selective HDAC inhibitors were designed by topology-based scaffold hopping structure- and ligand-based virtual screening. The top inhibitors (in terms of both binding affinity and selectivity) were subjected to structure-based in silico absorption distribution metabolism elimination and toxicity (ADMET) prediction which showed their druglikeness. Furthermore their docking complexes were submitted to molecular dynamics (MD) simulations to examine the stability of ligand binding modes. These potential isoform-selective HDAC inhibitors showed stable binding mode over time of the simulation. They can therefore serve as drug candidates or viable lead compounds for further modeling-based and experimental optimization towards the design of safe potent and selective HDAC inhibitors.

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