Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Identification of Potent and Novel Phosphatidylinositol 3-Kinase Catalytic Subunit Alpha Inhibitors: A Structure-Based Drug Design Approach

Head and neck squamous cell carcinoma (HNSCC), one of the most common causes of deaths due to cancers in Asian Countries and the sixth most common cause of cancer globally is a heterogeneous group of upper aerodigestive tract malignancies (Saleh et al. 2018). Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is reported to be commonly altered in many human tumors including HNSCC (Wen & Grandis 2015). Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases involved in the regulation of cell survival, growth and metabolism. PI3 Kinase phosphorylates PI(3,4)P2 (PIP2) converting it to PI(3,4,5)P3 (PIP3). Alterations such as mutation, gene amplification and overexpression of PIK3CA are commonly reported in HNSCC (García-Escudero et al. 2018). This leads to irregulated cell growth due to improper activation of p110α enzymatic activity. The present study aims to find out the potent and novel inhibitors of PIK3CA isoform of PI3Ks. Extensive database screening from NCI, Life Chemical ( Kinase Focused Library Similarity search, Kinase Screening Library, LC Kinase docking) and ChEMBL (KinaseSARfari) were performed. Computational approaches were employed to carry out a Structure-Based Drug Design study. Screened compounds from NCI and KinaseSARfari showed superior results and surpassed the benchmark compounds with huge differences. Top compounds of NCI (NSC 671560, NSC 729878) and KinaseSARfari (ChEMBL43781) reported GLIDE Gscore of -15.73 kcal/mol and -17.55 kcal/mol respectively whereas benchmark compounds from ChEMBL43781 had maximum GLIDE Gscore of -10.36 kcal/mol. Also, NVP-BYL719 (PDB:4JPS) the only reported selective inhibitor of PIK3CA has GLIDE Gscore -8.16 kcal/mol. To validate our results the top ranking compounds were docked using GOLD and the results were consistent. Along with GLIDE and GOLD scores, the binding affinity of the protein-ligand complex was also scored using X-Score program and found consistent with the previous results. A total of 10 compounds from all the screened libraries were selected and are currently under in-vitro investigation, for further validation of our findings.


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    García-Escudero R, Segrelles C, Dueñas M, et al (2018). Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway. Oral Oncol. 79:55-63.

Geet Madhukar
Naidu Subbarao*

School of Computational and Integrative Sciences
Jawaharlal Nehru University
New Delhi, India

Ph: (+91) 9687016818
Email: geet85_sit@jnu.ac.in