In-silico molecular modelling, MM/GBSA binding free energy and molecular dynamics simulation study of novel pyrido fused imidazo[4,5-c]quinolines as potential anti-tumor agents

Abstract

With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

Mechanistic Insights into the Binding of Boar Salivary Pheromones and Putative Molecule with Receptor Proteins: A Comparative Computational Approach

“…Finally, we calculated the free binding energies of the protein–ligand complexes. The lowest free binding energy was attributed to effective binding, in that pyrido-fused imidazo­[4,5- c ]­quinoline derivative binds effectively with phosphoinositide 3-kinase . In our study, pheromaxein–quinoline, SAL–quinoline, and VEGP–quinoline complexes exhibited low free binding energies.…”

“…The lowest free binding energy was attributed to effective binding, in that pyrido-fused imidazo [4,5-c]quinoline derivative binds effectively with phosphoinositide 3-kinase. 64 In our study, pheromaxein− quinoline, SAL−quinoline, and VEGP−quinoline complexes exhibited low free binding energies. However, the free energy of the OBP−quinoline was higher than those of the OBP− androstenone and OBP−androstenol.…”

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“…MM‐GBSA is a popular method for predicting binding free energy. Scoring functions are used to predict the lowest energy poses, which determine the accuracy of docking results, and to predict the binding affinity of ligands toward the protein 24,25 . The top 10 docked ligands from the XP docking results were used to calculate MM‐GBSA free energy using the variable‐dielectric generalized born (VSGB) solvation model.…”

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“…The binding free energy can reflect the interaction between the ligand small molecule and the receptor protein ( Wang et al., 2021 ). The interactions between ligand and receptor include both covalent and non-bonded interactions, but only non-bonded interactions (van der Waals interactions, electrostatic interactions and hydrogen bonding interactions) are generally present in complex systems of drug small molecules (ligands) and proteins (receptors) ( Dasmahapatra et al., 2022 ). Therefore, AMBER 18 was used to calculate the binding free energy by MM/GBSA method in this study ( Weng et al., 2019 ; Cao et al., 2022d ).…”