Graph Theoretical Analysis, Insilico Modeling and Formulation of Pyrimidine Nanoparticles as p38α MAP Kinases inhibitors: A Quantitative Proteomics Approach

Abstract

In this study, the optimized 4-(4-hydroxybenzyl)-2-amino-6-hydroxypyrimidine-5-carboxamide derivative was formulated as nanoparticles to evaluate for their anticancer activity. The response surface methodology (RSM) was performed with utilization of Box-Behnken statistical design (BBSD) to optimize the experimental conditions for identification of significant synthetic methodology. To explore the stability of the derivative was done by density functional theory (DFT). Graph theoretical analysis was introduced to identify the drug target p38α MAP Kinases and then insilico modeling was performed to provide straightforward information for further structural optimization. The experimental results under optimal experimental conditions obtained 74.55-76% yield of 4-(4-hydroxybenzyl)-2-amino-6-hydroxypyrimidine-5-carboxamide, 127oC melting point and Rf value 0.59 were well matched with the predicted results and this was gaining 95% of confidence level and suitability of RSM. The spectral data were reliable with the assigned structures of synthetic yields. The formulated nanoparticles were exhibited a good anticancer activity against used cancer cell line MCF7. Amusingly the observed docking scores and in-vitro anticancer activity was proving the compound significance and potential as a potent p38α inhibitor. Further, we have elucidated the mechanism of action at its functional level using label-free quantitative proteomics. Interestingly the observed results were indicating that the derived proteomics data involving in the alteration process in cancer-related regulatory pathways.

Graph theoretical analysis, in silico modeling, prediction of toxicity, metabolism and synthesis of novel 2‐(methyl/phenyl)‐3‐(4‐(5‐substituted‐1,3,4‐oxadiazol‐2‐yl) phenyl) quinazolin‐4(3H)‐ones as NMDA receptor inhibitor

“…Graph theoretical analysis (Kanehisa & Goto, ; Kunjiappan et al, ; Theivendren et al, ) was engaged by utilization of Kyoto Encyclopedia of Genes and Genomes database and network of protein interaction (hsa: 04724) in Homo sapiens was chosen to recognize the influential proteins.…”

“…The in silico modeling (Theivendren et al, ) of designed compounds were studied by GLIDE program (version 11, Schrodinger, LLC, New York, 2016) by extra precision (XP) mode. The Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank was used to retrieve N ‐methyl‐ d ‐aspartate receptor X‐ray crystal structure (PDB: 1PBQ).…”

Aphrodisiac Performance of Bioactive Compounds from Mimosa pudica Linn.: In Silico Molecular Docking and Dynamics Simulation Approach

“…The electronic effect of the drug-like molecule played an essential role in pharmacological activity. DFT is an effective theory for measuring the electronic states of atoms, molecules, and solids in terms of the three-dimensional electronic density system [49][50][51][52]. The main goal of DFT is to provide a quantitative understanding of material properties using the fundamental laws of quantum mechanics.…”

Graph Theoretical Network Analysis and Pharmacoinformatics-Based Investigation of Bioactive Compounds of Rasam (South Indian Recipe) Against Human Cancer

“…The signaling networks, such as genes, proteins, and enzymes, are shown in this perspective using graph theoretical network analysis. The selection of good target signaling network may be aided by graph theoretical network analysis 27 . It also gives data on the active site and molecular interactions of bioactive substances, which may help in the in silico molecular docking study.…”