Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor.

Amena Ali,Mohamed Jawed Ahsan,Magda H Abdellattif,Mostafa A Hussien,Abuzer Ali,Mohd Shahbaaz,Ola Abuali

doi:10.3390/molecules26195932

Abstract

In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R2 = 0.96 and Q2 = 0.57. Leave one out (LOO) cross-validation (R2 CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (−11.265, −10.532, −10.422, −10.827, −10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors

Highlights

Ligand development was performed with the LigPrep module using Maestro v12.1, which helped generate input structures for pharmacophore Alignment and Scoring Engine (PHASE) and Grid-Based Ligand Docking from Energetics (Glide) modules
A molecular docking study was performed to examine the possible interactions between protein and ligand molecules using the Schrödinger Glide module
The binding interactions of compound 43 were observed with PHE201, ASP158, GLY162, and PHE205, while in compound 56, interactions with PHE201, GLY202, and ASP158 amino acids were detected. These interactions are essential for TRAP1 inhibitory activity

Summary

Introduction

TRAP1 (tumor necrosis factor (TNF) receptor-associated protein 1) is a 90 kDa protein that encodes the mitochondrial chaperone protein Heat Shock Protein (Hsp90) and is closely related to tumorigenesis promotion in a variety of cancers [1,2]. TRAP1 helps maintain mitochondrial integrity, smoothing the progression of cell death against cellular stresses, which is obtained by reduced ROS production and reprogramming cellular metabolism. These two factors (maintaining mitochondrial integrity and reduced ROS production) allow cancer cells to adapt better to harsh tumor microenvironments [3,4,5].

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Conclusion