Novel inhibitor design for histone demethylase 1 (lsd1) enzyme using molecular modeling
Loading...
Files
Date
2019
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Kadir Has Üniversitesi
Abstract
Kanser bilinen hastalıkların en öldürücü ve ölüm nedenlerinin büyük bir kısmını kapsar. Kanseri tetikleyen birçok faktörün bilinmesine rağmen ana neden tam olarak henüz anlaşılmış değildir. Son yıllarlda yapılan çalışmlardan epigenetik süreçlerin kanser başlangıcında önemli rol oynadıkları bulunmuştur. DNA'nın metilasyonu ve histon modifikasyonları en yaygın sistemler olarak epigenetik değişimlere sebep olurlar. Histon lisinspesifik demetilaz (LSD1) gen susturmada, DNA transkripsiyonunda, DNA replikasonunda ve DNA hasar tamiri gibi geniş bir yelpazede epigenetik proseslerde görev almaktadır. Bunların yayında LSD1 enziminin seviyesi AML, meme kanseri, prostat kanser ve birçok diğer kanser tiplerinde anlamlı bir şekilde yükseldiği görülmüştür. LSD1 enzimine etkili ve güvenli inhibitor tasarlanması için yoğun bir ilgi çekmemesine rağmen sadece çok seçici olmayan iki ilaç; 2-[4-methoxy-phenyl]cyclopropylamine ve tranylcypromine onay almıştır. Çalışmamızın amacı in silico yöntemle daha seçici ve potansiyeli yüksek özgün LSD1 inhibitörleri tasarlamak ve geliştirmektir. Sanal tarama ve yapıya dayalı farmakofor modelleme yaklaşımları kullanılarak potansiyel lider bileşikler elde edilmiştir. Çalışmada Zinc 15 veri bankasında bulunan 60,000 bileşik kullanılmıştır. PyRx (autodockVina) kullanılarak değişik analizler sonucunda bağlanma enerjileri -9 kcal\mol 'dan daha iyi birkaç yüz bileşik elde edilebilmiştir. Bu yaklaşımlardan LSD1 enzimini inhibe eden 20 bileşik bağlanma enerjileri ve 2D resimlerden enzimin aktif kısmına konumlanma gibi istenilen özellikleri karşılayabilecek niteliklere sahip olduğu tespit edilmiştir. Seçilen 20 bileşiklerin farmakokinetik özellikler ADMET testleri uygulanarak kontrol edilmiştir.
Cancer is the most lethal disease among all known diseases and comprises the largest segment of death causes. Although, many factors have direct involvement in cancer triggering, still the complete understanding behind the main cause of cancer is unrevealed. Recent studies have shown that the epigenetic process plays an ultimate role in cancer initiation. DNA methylation and histone modification are considered the most common systems that might cause epigenetic changes. Histone lysine specific demethylase (LDS1) has proved to have a significant impact and involvement in a wide range in the epigenetic process including gene silencing, DNA transcription, DNA replication, and DNA repairing. In addition, it has been noticed that LSD1 enzyme level is increased in many cancer types such as AML, breast cancer, prostate cancer, and many other cancers. However, extensive attention has been drowning toward developing a safe and effective LSD1 inhibitors, meanwhile, only two drugs are described as LSD1 inhibitors 2-[4-methoxy-phenyl] cyclopropylamine and Tranylcypromine which they are not very selective. Therefore, the main objective of the research is to design and develop specific and selective inhibitors for LSD1 using molecular modeling in silico. Potential leads compounds were obtained using virtual screening and structure base pharmacophore. Zinc15 database which contains 60,000 compounds were screened. As results of different analysis using PyRx (autodock), several hundred compounds shown better binding energy values than -9kcal/.mol. However, 20 compounds out of total obtained compounds shown significant binding energy, and desirable chemical interaction at the active site of the enzyme. Pharmacokinetics properties of the 20 selected compounds were investigated by applying ADMET prediction assay. All 20 compounds passed the ADMET prediction criteria and they can serve as drug candidates for advance optimization across the design of safe, effective, and selective LSD1 inhibitors.
Cancer is the most lethal disease among all known diseases and comprises the largest segment of death causes. Although, many factors have direct involvement in cancer triggering, still the complete understanding behind the main cause of cancer is unrevealed. Recent studies have shown that the epigenetic process plays an ultimate role in cancer initiation. DNA methylation and histone modification are considered the most common systems that might cause epigenetic changes. Histone lysine specific demethylase (LDS1) has proved to have a significant impact and involvement in a wide range in the epigenetic process including gene silencing, DNA transcription, DNA replication, and DNA repairing. In addition, it has been noticed that LSD1 enzyme level is increased in many cancer types such as AML, breast cancer, prostate cancer, and many other cancers. However, extensive attention has been drowning toward developing a safe and effective LSD1 inhibitors, meanwhile, only two drugs are described as LSD1 inhibitors 2-[4-methoxy-phenyl] cyclopropylamine and Tranylcypromine which they are not very selective. Therefore, the main objective of the research is to design and develop specific and selective inhibitors for LSD1 using molecular modeling in silico. Potential leads compounds were obtained using virtual screening and structure base pharmacophore. Zinc15 database which contains 60,000 compounds were screened. As results of different analysis using PyRx (autodock), several hundred compounds shown better binding energy values than -9kcal/.mol. However, 20 compounds out of total obtained compounds shown significant binding energy, and desirable chemical interaction at the active site of the enzyme. Pharmacokinetics properties of the 20 selected compounds were investigated by applying ADMET prediction assay. All 20 compounds passed the ADMET prediction criteria and they can serve as drug candidates for advance optimization across the design of safe, effective, and selective LSD1 inhibitors.