Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor: Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

Abstract

Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen bond acceptors and two hydrophobic features were proposed as a pharmacophore model using LASW1976 structure. The model was then validated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) and GH score. It was used to screen new molecules in the ZINC database, which resulted in 599 hits. All 599 hits were then docked into PI3Kδ protein, and five best hits were submitted to 50 ns molecular dynamics simulations. Each hit complexed with PI3Kδ underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Furthermore, prediction of the binding free energy using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method showed that five hits, i.e., Lig25/ZINC253496376, Lig682/ZINC98047241, Lig449/ZINC85878047, Lig554/ZINC253389510, and Lig199/ZINC12638303, had lower binding energy compared to LASW1976. This result indicated their potentials as new inhibitors of PI3Kδ.

Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

“…The advantage of molecular docking in designing a new inhibitor does not require a large amount of data or only employ some molecules as the lead compounds. Previous research had designed quinazoline derivative compounds by using quantitative structureactivity relationship (QSAR) analysis in large data compounds [16][17][18] and studied the stability of hydrogen bond formed through compound and protein [19][20][21][22]. However, designing a new EGFR inhibitor using a molecular docking approach of the lead compounds such as erlotinib, afatinib, and WZ4002 has never been done.…”

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)–protein interactions, parameterization, and validation of a new force field

“…As previous commented, the simulations were divided into four steps, namely: minimization, heating, equilibrium, and production. To perform the four steps, the force field “leaprc.ff14SB” was used to simulate the protein [ 65 , 66 ]. On the other hand, to simulate the vanadium complex, the force field developed and validated in this work was used.…”

“…To counterbalance the charges of the amino acids in the protein, the neutral pH was considered, and the program leap was used. All four steps were performed considering the work of Arba et al [ 65 ] and Farrokhzadeh et al [ 66 ].…”

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)–protein interactions, parameterization, and validation of a new force field

“…As previous commented, the simulations were divided into four steps, namely: minimization, heating, equilibrium, and production. To perform the four steps, the force field "leaprc.ff14SB" was used to simulate the protein [60,61]. On the other hand, to simulate the vanadium complex, the force field developed and validated in this work was used.…”

“…To counterbalance the charges of the amino acids in the protein, the neutral pH was considered, and the program leap was used. All four steps were performed considering the work of Arba et al [60] and Farrokhzadeh et al [61].…”