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

Yıl 2022, , 957 - 966, 01.06.2022

Deryanur Kılıç

https://doi.org/10.21597/jist.1079867

Öz

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.

Anahtar Kelimeler

PI3Kγ, virtual screening, inhibitör

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

Öz

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.

Anahtar Kelimeler

PI3Kγ, sanal tarama, inhibitör

Kaynakça

• Cantley LC, 2002. The Phosphoinositide 3-Kinase Pathway. Science 296, 1655−1657.
• Come JH, Collier PN, Henderson JA, Pierce AC, Davies RJ, Le Tiran A, O’Dowd H, Bandarage UK, Cao J, Deininger D, Grey R, 2018. Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase Γ (PI3Kγ) Inhibitors with Potential For The Treatment of Multiple Sclerosis (MS). Journal of Medicinal Chemistry, 61(12): 5245-5256.
• Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shaw DE, Shelley M, Perry JK, Francis P, Shenkin PS, 2004. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. Journal of Medicine Chemistry, 47(7): 1739–1749.
• Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT, 2006. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes. Journal of Medicine Chemistry, 49(21): 6177–6196.
• Fritsch R, de Krijger I, Fritsch K, George R, Reason B, Kumar MS, Diefenbacher M, Stamp G, Downward J, 2013. RAS and RHO Families of Gtpases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms. Cell, 153(5): 1050−1063.
• Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL, 2004.Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening. Journal of Medicine Chemistry, 47(7): 1750–1759.
• Hawkins PT, Anderson KE, Davidson K, Stephens LR, 2006. Signalling Through Class I PI3Ks in Mammalian Cells. Biochemistry Society Transactions. 34(5): 647−662.
• Jacobson MP, Friesner RA, Xiang Z, Honig B, 2002. On the Role of Crystal Packing Forces in Determining Protein Sidechain Conformations. Journal of Molecular Biology, 320(3): 597-608.
• Li D, Park D, Abdul-Muneer PM, Xu B, Wang H, Xing B, Wu D, Li S, 2013. PI3Kγ Inhibition Alleviates Symptoms and Increases Axon Number in Experimental Autoimmune Encephalomyelitis Mice. Neuroscience, 253, 89−99.
• Okkenhaug K, Graupera M, Vanhaesebroeck B, 2016. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discovery, 6, 1090− 1105.
• Perry VH, Holmes C, 2014. Microglial Priming in Neuro- Degenerative Disease. Nature Reviews Neurology, 10, 217−224.
• Porcu P, Flinn I, Kahl BS, Horwitz SM, Oki Y, Byrd J C, Sweeney J, Allen K, FaiaK, Ni M, Stern HM, Kelly P, O’Brien S, 2014. Clinical Activity of Duvelisib (IPI-145), A Phosphoinositide- 3-Kinase-Δ,Γ Inhibitor, in Patients Previously Treated with İbrutinib. Blood, 124(21), 3335.
• Rommel C, Camps M, Ji H, 2007. PI3Kδ and PI3Kγ: Partners in Crime in Inflammation in Rheumatoid Arthritis And Beyond? Nature Reviews Immunology, 7(11): 191−201.
• Sabbah D. A, Vennerstrom J.L, & Zhong, H. 2010. Docking Studies on Isoform-Specific Inhibition of Phosphoinositide-3-Kinases. Journal of Chemical Information and Modeling, 50(10): 1887-1898. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W, 2013. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments, Journal of Computer-Aided Molecular Design, 27(3), 221-234.
• Taha MO, Al-Sha'er MA, Khanfar MA, Al-Nadaf AH, 2014. Discovery of Nanomolar Phosphoinositide 3-Kinase Gamma (PI3Kγ) Inhibitors Using Ligand-Based Modeling and Virtual Screening Followed by in vitro Analysis. European Journal of Medicinal Chemistry, 84, 454-465.
• Tang J, Zhu J, Yu Y, Zhang Z, Chen G, Zhou X, Qiao C, Hou T, Mao X, 2014. A Virtual Screen Identified C96 as A Novel Inhibitor of Phosphatidylinositol 3-Kinase that Displays Potent Preclinical Activity Against Multiple Myeloma in vitro and in vivo. Oncotarget, 5(11): 3836-3848.
• Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B, 2010. The Emerging Mechanisms of Isoform-Specific PI3K Signaling. Nature Reviews Molecular Cell Biology,11, 329−341.
• Zhu J, Li K, Xu L, Cai Y, Chen Y, Zhao X, Li H, Huang G, Jin J, 2022. Discovery of Novel Selective PI3Kγ Inhibitors Through Combining Machine Learning-Based Virtual Screening with Multiple Protein Structures and Bio-Evaluation. Journal of Advanced Research, 36, 1-13.
• Zhu J, Wang M, Yu Y, Qi H, Han K, Tang J, Zhang Z, Zeng Y, Cao B, Qiao C, Zhang H, 2019. Correction: A Novel PI3K Inhibitor PIK-C98 Displays Potent Preclinical Activity Against Multiple Myeloma. Oncotarget, 10 (65): 7010-7011.