title: Checking the STEP-Associated Trafficking and Internalization of Glutamate Receptors for Reduced Cognitive Deficits: A Machine Learning Approach-Based Cheminformatics Study and Its Application for Drug Repurposing.
abstract: BACKGROUND
  Alzheimer's disease, a lethal neurodegenerative disorder that leads to progressive memory loss, is the most common form of dementia. Owing to the complexity of the disease, its root cause still remains unclear. The existing anti-Alzheimer's drugs are unable to cure the disease while the current therapeutic options have provided only limited help in restoring moderate memory and remain ineffective at restricting the disease's progression. The striatal-enriched protein tyrosine phosphatase (STEP) has been shown to be involved in the internalization of the receptor, N-methyl D-aspartate (NMDR) and thus is associated with the disease. The present study was performed using machine learning algorithms, docking protocol and molecular dynamics (MD) simulations to develop STEP inhibitors, which could be novel anti-Alzheimer's molecules.
  
  
  METHODS
  The present study deals with the generation of computational predictive models based on chemical descriptors of compounds using machine learning approaches followed by substructure fragment analysis. To perform this analysis, the 2D molecular descriptors were generated and machine learning algorithms (Naïve Bayes, Random Forest and Sequential Minimization Optimization) were utilized. The binding mechanisms and the molecular interactions between the predicted active compounds and the target protein were modelled using docking methods. Further, the stability of the protein-ligand complex was evaluated using MD simulation studies. The substructure fragment analysis was performed using Substructure fingerprint (SubFp), which was further explored using a predefined dictionary.
  
  
  RESULTS
  The present study demonstrates that the computational methodology used can be employed to examine the biological activities of small molecules and prioritize them for experimental screening. Large unscreened chemical libraries can be screened to identify potential novel hits and accelerate the drug discovery process. Additionally, the chemical libraries can be searched for significant substructure patterns as reported in the present study, thus possibly contributing to the activity of these molecules.
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, India.
authors.forename: Asheesh
authors.initials: A
authors.lastname: Shanker
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D000069550:Machine Learning; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor