Identification of Potential Dual Negative Allosteric Modulators of Group I mGluR Family: A Shape Based Screening, ADME Prediction, Induced Fit Docking and Molecular Dynamics Approach Against Neurodegenerative Diseases

Abstract

Background: Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are a class of C GPCRs that play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain involved in cognition, learning, memory, and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, X-fragile syndrome, anxiety, depression, etc., hence these receptors are high profile targets for pharmaceutical industries. Objective: The objective of our study is to find the novel dual negative allosteric modulators to regulate both mGluR1 and mGluR5. Methods: In this study, shape screening protocol was used to find the dual negative allosteric modulators for both mGluR1 and mGluR5 followed by ADME prediction, induced-fit docking (IFD) and molecular dynamics simulations. Further, DFT analysis and MESP studies were carried out for the selected compounds. Results: Around 247 compounds were obtained from the eMolecules database and clustered through the CANVAS module and filtered with ADME properties. Furthermore, IFD revealed that the top four compounds (16059796, 25004252, 4667236 and 11670690) having good protein-ligand interactions and binding free energies. The molecular electrostatic potential of the top compounds shows interactions in the amine group and the oxygen atom in the negative potential regions. Finally, molecular dynamics simulations were performed with all the selected as well as the reported compound 29 indicates that the screened hits have better stability of protein ligand complex. Conclusion: Hence, from the results, it is evident that top hits 16059796, 25004252, 4667236 and 11670690 could be a novel and potent dual negative allosteric modulators for mGluR1 and mGluR5.

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…However, more models should be constructed to cover more diverse chemical space if different shapes are available (Perez-Nueno and Ritchie, 2011 ), particularly for highly flexible proteins. Some studies using the shape-focused method have been reported in recent years (Reddy et al, 2013 ; Chen et al, 2015 ; Kumar et al, 2015 ; Prabhu and Singh, 2019 ). For example, Chen et al ( 2015 ) presented a shape-based virtual screening to find new cores for the design of acetylcholinesterase (AChE) inhibitors.…”

Strategies to apply 3Rs in preclinical testing

“…In the drug development process, parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) must be assessed since they determine the potential effect of the compound under study. In this regard, molecular modeling allows the prediction of ADMET properties through the application of different approaches such as pharmacophore modelling, molecular docking, dynamic simulations, and quantum mechanics calculation 26–30 …”

Targeting the C-Terminal Domain Small Phosphatase 1

“…These characteristics will help with finding a novel targeting strategy to precisely regulate CTDSP1's activity. The field of drug designing has been rapidly advancing in recent decades, and many new state-ofthe-art technologies and methods have been discovered [20,[104][105][106][107][108][109][110][111][112][113][114]. Well rationalized structural information of receptor proteins and ligand chemicals is the essential requirement for drug designing.…”

“…Numerous software tools for protein-ligand dockings, such as Autodock, DOCK 4.0, GOLD, Flex-X, ICM, SLIDE, GLIDE, and DeepBindRG, were developed based on various scoring functions, including empirical, knowledge-based, and machine learning, and are summarized in Table 2 [50,[115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130]. The field of drug designing has been rapidly advancing in recent decades, and many new state-of-the-art technologies and methods have been discovered [20,[104][105][106][107][108][109][110][111][112][113][114]. Well rationalized structural information of receptor proteins and ligand chemicals is the essential requirement for drug designing.…”

“…The allosteric docking technique gained importance, since these vital targets were operated effectively. Allosteric docking involves a few crucial steps like allosteric binding site identification, analysis, and optimization [104,105,143]. The allosteric binding sites are identified through the literature and database searches, cavity finding, blind docking, coevolution, and so forth.…”