Publication: Alzheimer tedavisine yönelik yeni üre/ karbamat türevlerinin in siliko tasarımı ve sentezi
Abstract
Alzheimer hastalığı (AH), basit hafıza kaybından ağır demansa kadar ilerleyebilen, çok faktörlü kronik nörodejaneratif bir hastalıktır. Kullanılan ilaçların hastalığı tedavi etmede yetersiz oluşu ve çeşitli yan etkilerinin görülmesi nedeniyle yeni ilaç potansiyeli gösteren bileşiklerin keşfine yönelik çalışmalara ihtiyaç vardır. Hastalığın kompleks patafizyolojisi nedeniyle çoklu hedef mantığına dayalı ilaç tasarımı son yıllarda önem kazanmıştır. AH tedavisinde kullanılan ilaçlar genellikle kolinerjik fonksiyonları olduğu bilinen kolinesteraz enzimlerini (ChE) inhibe etmeye yöneliktir. Monoamin oksidaz (MAO) enzimlerinin de deaminasyon mekanizması ile beyinde oksidatif strese neden olması ve AH’ye neden olduğu bilinen amiloid-β fibril oluşumunu arttırması nedeniyle hastalığa sebep olduğu düşünülmektedir. Bunların yanında, amiloid bağlayıcı alkol dehidrojenaz (ABAD) enziminin amiloid-β peptidini bağladığı ve hücrede toksik etki gösterdiği bilinmektedir. Bu tez çalışmasında, bilinen inhibitörlerin farmakofor gruplarını taşıyan yeni tasarlanmış karbamat, tiyokarbamat, üre, tiyoüre ve tiyoürelerin halkalaştırılması ile elde edilen tiyazolidin halkası içeren 211 adet orijinal bileşiğin farmakokinetik ve farmakodinamik özellikleri in siliko yöntemlerle incelenmiştir. Tüm bileşiklerin ADME tahminleri yapılmış, moleküler doking ile AChE, BuChE, MAO-A, MAO-B ve ABAD enzimlerine bağlanma enerjieri hesaplanmıştır. Seçilen etkin inhibitörlerin ilgili enzim komplekslerinin kararlılıkları moleküler dinamik simülasyonları ile analiz edilmiştir. Bileşiklerin ilgili enzimlerin aktif bölgelerindeki bağlanma pozları ve bağlanma etkileşimleri tespit edilmiştir. Ayrıca, tiyazolidin yapısı içeren hemiaminal bileşiklerinin kararlılığına etki eden faktörler hesapsal yöntemler ile incelenmiş ve bazı tiyokarbamat bileşikleri sentezlenip yapıları spektroskopik yöntemlerle aydınlatılmıştır. Üre ve karbamat türevi içeren bileşiklerin çoğu AChE, BuChE ve MAO-B, tiyazolidin halkası içeren bileşikler ise AChE ve BuChE enzimlerine yüksek afinite ile bağlanarak çoklu inhibisyon etkisi göstermiştir. Çeşitli ilaç olabilirlik kriterlerini sağlayan ve kan beyin engelini geçebileceği tespit edilen bu bileşikler potansiyel ilaç adayları olarak önerilmiştir. Yapılan çalışmaların in vitro ve in vivo deneylere ışık tutmaları beklenmektedir.
Alzheimer's disease (AD) is a multifactorial chronic neurodegenerative disease that can progress from simple memory loss to severe dementia. Due to the insufficiency of the drugs used to treat the disease and various side effects, there is a need for studies to discover new potential drug compounds. Due to the complex pathophysiology of the disease, drug design based on multi-target logic has gained importance in recent years. Drugs used in the treatment of AD are generally directed to inhibit cholinesterase enzymes (ChE), which are known to have cholinergic functions. It is thought that the deamination mechanism of monoamine oxidase (MAO) enzymes causes and increases the formation of amyloid-β fibril, which is known to cause AD. In addition, the enzyme amyloid-binding alcohol dehydrogenase (ABAD) is known to bind amyloid-β peptide and show toxic effects in the cell. In this thesis, the pharmacokinetic and pharmacodynamic properties of 211 newly designed original carbamate, thiocarbamate, urea, thiourea and thiazolidine derivatives containing pharmacophore groups of known inhibitors were investigated by in silico methods. ADME properties were predicted for all compounds and their binding energies to AChE, BuChE, MAO-A, MAO-B, ABAD enzymes were calculated by molecular docking. The stability of the enzyme complexes of the selected inhibitors was analyzed by molecular dynamics simulations. The binding poses and binding interactions of the potent compounds in the active sites of the related enzymes were resolved. The factors affecting the stability of hemiaminal compounds containing thiazolidine ring were investigated by computational methods. Some thiocarbamate compounds were synthesized and their chemical structures were elucidated by spectroscopic methods. Most of the urea and carbamate derivatives showed multi-target effects by binding with high affinity to AChE, BuChE and MAO-B, while thiazolidine derivatives showed high affinity to AChE and BuChE enzymes. These compounds which have good drug-like properties and can cross the blood brain barrier were proposed as potential drug candidates. These studies are expected to shed light on in vitro and in vivo experiments.
Alzheimer's disease (AD) is a multifactorial chronic neurodegenerative disease that can progress from simple memory loss to severe dementia. Due to the insufficiency of the drugs used to treat the disease and various side effects, there is a need for studies to discover new potential drug compounds. Due to the complex pathophysiology of the disease, drug design based on multi-target logic has gained importance in recent years. Drugs used in the treatment of AD are generally directed to inhibit cholinesterase enzymes (ChE), which are known to have cholinergic functions. It is thought that the deamination mechanism of monoamine oxidase (MAO) enzymes causes and increases the formation of amyloid-β fibril, which is known to cause AD. In addition, the enzyme amyloid-binding alcohol dehydrogenase (ABAD) is known to bind amyloid-β peptide and show toxic effects in the cell. In this thesis, the pharmacokinetic and pharmacodynamic properties of 211 newly designed original carbamate, thiocarbamate, urea, thiourea and thiazolidine derivatives containing pharmacophore groups of known inhibitors were investigated by in silico methods. ADME properties were predicted for all compounds and their binding energies to AChE, BuChE, MAO-A, MAO-B, ABAD enzymes were calculated by molecular docking. The stability of the enzyme complexes of the selected inhibitors was analyzed by molecular dynamics simulations. The binding poses and binding interactions of the potent compounds in the active sites of the related enzymes were resolved. The factors affecting the stability of hemiaminal compounds containing thiazolidine ring were investigated by computational methods. Some thiocarbamate compounds were synthesized and their chemical structures were elucidated by spectroscopic methods. Most of the urea and carbamate derivatives showed multi-target effects by binding with high affinity to AChE, BuChE and MAO-B, while thiazolidine derivatives showed high affinity to AChE and BuChE enzymes. These compounds which have good drug-like properties and can cross the blood brain barrier were proposed as potential drug candidates. These studies are expected to shed light on in vitro and in vivo experiments.
Description
Keywords
adme, akılcı ilaç tasarımı, Alzheimer hastalığı, Alzheimer's disease, Chemistry, Organic, computational chemistry, density funtional theory, hesapsal kimya, Kimya, Kimya, Organik, molecular docking, molecular dynamic simulation, moleküler dinamik simülasyonları, moleküler doking, rational drug design, yoğunluk fonksiyoneli teorisi Chemistry