Iqbal, Saleem and Potharaju, Raju and Naveen, S. and Lokanath, N. K. and Mohanakrishnan, Arasambattu K. and Gunasekaran, Krishnasamy (2021) Design, crystal structure determination, molecular dynamic simulation and MMGBSA calculations of novel p38-alpha MAPK inhibitors for combating Alzheimer's disease. Journal of Biomolecular Structure and Dynamics.
Full text not available from this repository. (Request a copy)Abstract
The hallmark of the Alzheimer's disease (AD) is the accumulation of aggregated, misfolded proteins. The cause for this accumulation is increased production of misfolded proteins and impaired clearance of them. Amyloid aggregation and tau hyperphosphorylation are the two proteinopathies which accomplish deprivation of cell and tissue hemostasis during neuropathological process of the AD, as a result of which progressive neuronal degeneration and the loss of cognitive functions. p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in both the events associated with AD: tau protein phosphorylation and inflammation. p38 alpha MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Clinical and preclinical evidence implicates the stress related kinase p38 alpha MAPK as a potential neurotherapeutic target. Drug design of p38 alpha MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here we have carried out the synthesis of phenyl sulfonamide derivatives Sulfo (I) and Sulfo (II). Crystal structures of Sulfo (I) and Sulfo (II) were solved by direct methods using SHELXS-97. Sulfo (I) and Sulfo (II) have R(int)values of 0.0283 and 0.0660, respectively, indicating good quality of crystals and investigated their ability against p38 alpha MAPK. Docking studies revealed that the Sulfo (I) had better binding affinity (-62.24 kcal/mol) as compared to Sulfo (II) and cocrystal having binding affinity of -54.61 kcal/mol and -59.84 kcal/mol, respectively. Molecular dynamics simulation studies of Sulfo (I) and cocrystal of p38 alpha MAPK suggest that during the course of 30 ns simulation run, compound Sulfo (I) attained stability, substantiating the consistency of its binding to p38 alpha MAPK compared to cocrystal. Binding free energy analysis suggests that the compound Sulfo (I) is better than the cocrystal. Thus, this study corroborates the therapeutic potential of synthesized Sulfo (I) in combatting AD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Alzheimer's disease; tau hyperphosphorylation; phenyl sulfonamides; p38 alpha MAPK inhibitors; molecular dynamics simulations; neuroinflammation |
| Subjects: | D Physical Science > Physics |
| Divisions: | Department of > Physics |
| Depositing User: | Mr Umendra uom |
| Date Deposited: | 18 May 2022 10:15 |
| Last Modified: | 18 May 2022 10:15 |
| URI: | http://eprints.uni-mysore.ac.in/id/eprint/17220 |
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