Determination of Novel Selective Phosfoinositide 3-Kinase Gamma Inhibitors by In Silico Approaches

Abstract

In view of the high sequence homology of the ATP binding sites between the lipid kinase phosphoinositide 3-kinase (PI3K) isoforms, selective inhibitors of PI3Kγ have been developed. In this study, R-group enumeration library screening was performed to increase the binding affinity of the known selective inhibitor to the PI3Kγ enzyme. Virtual screening was performed using Glide SP/XP docking protocols. The interactions between the molecules identified by screening and the PI3Kγ protein were examined. In addition, ADME analyzes of these molecules were performed and hit molecules (3, 4) were determined. It was determined by in silico approaches that these hit molecules could be potential PI3Kγ inhibitors. In addition, these hit molecules can be used as lead to design other molecules targeting the PI3Kγ protein.

Keywords

• PI3Kγ
• virtual screening
• inhibitör

Yeni Seçici Fosfoinositid 3-Kinaz Gama İnhibitörlerin İn Siliko Yaklaşımlarla Belirlenmesi

Abstract

Lipid kinaz fosfoinositid 3-kinaz (PI3K) izoformları arasındaki ATP bağlanma bölgelerinin yüksek sekans homolojisi göz önüne alınarak, PI3Kγ 'nin seçici inhibitörleri geliştirilmiştir. Bu çalışmada ise bilinen seçici inhibitörünün PI3Kγ enzimine bağlanma afinitesini arttırmak için R-grubu enumerasyon kitaplık taraması gerçekleştirildi. Glide SP/XP doking protokollerine tabi tutularak sanal tarama yapıldı. Taramayla belirlenen moleküller ile PI3Kγ proteini arasındaki etkileşimler incelendi. Ayrıca bu moleküllerin ADME analizleri yapıldı ve hedef moleküller (3, 4) belirlendi. Bu hedef moleküllerin potansiyel PI3Kγ seçici inhibitörleri olabileceği in siliko yaklaşımlarla belirlendi. Ayrıca bu hedef moleküller, PI3Kγ proteinini hedef alan diğer moleküllerin tasarlanması için öncü moleküller olarak da kullanılabilir.

Keywords

• PI3Kγ
• sanal tarama
• inhibitör

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