Identification of Peregrin inhibitors-modulators by harnessing the computational prowess of molecular simulation and machine learning algorithms

Abstract

Peregrin is marked as a potential drug target due to its pivotal role in the epigenetic maintenance of cellular metabolism. It is counted among those of the bromodomain-containing protein family. The protein binds to the acetylated lysine of N-terminus histone proteins of the nucleosomes. This bound form neutralizes the otherwise positively charged histone and, thus, crucially impacts the DNA replication mechanism. In several diseases like cancer, bone loss, and leukemia, this peregrin binding impacts the genes’ overexpression. Hence, the present study, computational screening of the bromodomain-specific inhibitors from a library of 5430 compounds retrieved from the ChemDiv database. Two different scoring functions based molecular docking studies have been employed for molecular interaction analysis. Followed by an artificial intelligence-based absolute binding affinity prediction has been confirmed through KDeep, which follows a machine learning step to obtain a precise binding energy score for the set of best compounds in the screening process. The resultant compounds were then screened for pharmacokinetics and drug-likeliness properties. Using molecular dynamics (MD) simulation analysis, the dynamic behavior of the four suggested compounds and Peregrin has been investigated for a 100 ns period. Identified compounds are found to be sufficiently effective in holding their strong interaction affinity toward Peregrin for an adequate time span, and structural integrity is also found to be comparable with the standard compound considered in the study. Mostly, all four potent compounds (K788-9421, S357-0084, S357-0893, S357-0915) are hydrophobic and evaluated for thermodynamics property analysis using MM-GBSA and free energy landscape (FEL) calculations. However, among all, K788-9421 shows comparatively better and energetically most favorable interactions with peregrin. Overall, study findings can lead to further research in developing next-generation broad-spectrum Peregrin inhibitors-modulators; they need extensive experimental validation for considering the compounds for clinical-trial application for being an excellent drug-candidate entity against Peregrin protein.