TARGETTING THE 3BGQ - PIM1 KINASE INTERACTION WITH A SERIES OF NOVEL DITHIOCARBAMATE SUBSTITUTED 2-OXOINDOLE DERIVATIVES - IN SILICO STUDIES

Year 2022, Volume: 46 Issue: 1, 86 - 102, 29.01.2022

Muni Sireesha Sunkara , Saritha Jyostna Tangeda , Dharani Annepally Donna Kanthi Bıtla Sushma Boppy , Pallavı Chidurala , Jhansi Chıluka

https://doi.org/10.33483/jfpau.983848

Abstract

Objective: Cancer is the major cause of mortality in most of the developing countries. Enormous chemotherapeutic agents developed are still need improvements in survival rates and quality of life for cancer patients. Pro-viral Integration site of Moloney murine leukemia virus (PIM1) is a family of serine/threonine kinase, regulated by calcium/calmudulin have been identified as a unique molecular target in oncogenesis. PIM1 has significant role in cell cycle regulation, cell survival, apoptosis, cellular senescence, drug resistance and it is emerging as a potential biomarker in number of human malignancies. Today many interesting PIM1 inhibitors are developed and few withdrawn from phase1 and 2 clinical trials, due to lack of bioavailability and toxicity. Hence the purpose of the present study is to develop more potent and less toxic compounds.
Material and Method: A series of novel 2-oxindoles with dithiocarbamates were designed as PIM1 inhibitors. All molecules were subjected to Molsoft, Molinspiration, Swiss ADME and pkCSM to predict their molecular properties which are important for drug candidate. Further, in order to find the binding affinity of designed molecules with PIM1 kinase protein and to rationalize their anticancer activity, molecular docking study was performed.
Result and Discussion: Results revealed that all designed compounds fulfilled the criteria for good oral bioavailability, low toxicity and the potential inhibitory activities. All of them were docked into active site of PIM1 kinase with AutoDock Vina software. In conclusion, according to the binding energy values, compound 16 and 24 showed equivalent dock score -9.7 kcal/mol which are comparable with previously reported compounds AZ1208 and SGI 1776. This finding will help the researchers in the design of a better drug for the treatment of cancer.

Keywords

AutoDock Vina, dithiocarbamate, PIM1 Kinase, QSAR, 2-oxindole

Supporting Institution

Sarojini Naidu Vanita Pharmacy Maha Vidyalaya, Tarnaka, Hyderabad.

3BGQ - PIM1 KİNAZ ETKİLEŞİMİNİ HEDEF ALAN YENİ DİTİYOKARBAMAT İLE SÜBSTİTÜE 2-OKSOİNDOL TÜREVLERİNİN İN SİLİKO ÇALIŞMALARI

Abstract

Amaç: Kanser, gelişmekte olan ülkelerin çoğunda başlıca ölüm nedenidir. Geliştirilen muazzam kemoterapötik ajanların, kanser hastalarının hayatta kalma oranları ve yaşam kaliteleri açısından hala iyileştirilmeleri gerekmektedir. Moloney murin lösemi virüsünün (PIM1) pro-viral entegrasyon bölgesi, kalsiyum/kalmudulin tarafından düzenlenen bir serin/treonin kinaz ailesidir, onkogenezde benzersiz bir moleküler hedef olarak tanımlanmıştır. PIM1 hücre döngüsü düzenlenmesi, hücre sağkalımı, apoptozu, hücresel yaşlanması ve ilaç direncinde önemli bir role sahiptir ve insan malignitelerinin sayısında potansiyel bir biyobelirteç olarak ortaya çıkmaktadır. Bugün birçok ilginç PIM1 inhibitörü geliştirildi ve biyoyararlanım ve toksisite eksikliği nedeniyle birkaçı faz 1 ve 2 klinik çalışmalardan çekildi. Dolayısıyla bu çalışmanın amacı, daha güçlü ve daha az toksik bileşikler geliştirmektir.
Gereç ve Yöntem: Ditiyokarbamat içeren bir seri yeni 2-oksindoller PIM1 inhibitörü olarak tasarlandı. Tüm moleküllerin ilaç adayı için önemli olan moleküler özelliklerini tahmin etmek için Molsoft, Molinspiration, Swiss ADME ve pkCSM programları kullanıldı. Ayrıca, tasarlanan bileşiklerin PIM1 kinaz proteini ile bağlanma afinitelerini bulmak ve antikanser aktivitelerini rasyonalize etmek için, moleküler yerleştirme çalışması yapıldı.
Sonuç ve Tartışma: Sonuçlar, tasarlanan tüm bileşiklerin iyi oral biyoyararlanım, düşük toksisite ve potansiyel inhibitör aktiviteler için kriterleri karşıladığını ortaya koymaktadır. Tüm bileşiklerin PIM1 kinazın aktif bölgesine yerleştirilmesi Auto DockVina yazılımı ile gerçekleştirildi. Sonuç olarak, bağlanma enerjisi değerlerine göre, bileşik 16 ve 24 daha önce bildirilen AZ1208 ve SGI 1776 bileşikleri ile karşılaştırılabilir eşdeğer dock skoru -9.7 Kcal/mol gösterdi. Bu bulgu, araştırmacılara kanser tedavisi için daha iyi bir ilacın tasarımında yardımcı olacaktır.

Keywords

AutoDock Vina, ditiyokarbamat, PIM1 Kinaz, QSAR, 2-oksoindol

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