Iqbal, S and Potharaju, R and Naveen, S and Lokanath, NK and Mohanakrishnan, AK and Gunasekaran, K (2021) Design, crystal structure determination, molecular dynamic simulation and MMGBSA calculations of novel p38-alpha MAPK inhibitors for combating Alzheimer�s disease. In: Journal of Biomolecular Structure and Dynamics .
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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. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Clinical and preclinical evidence implicates the stress related kinase p38α MAPK as a potential neurotherapeutic target. Drug design of p38α 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 Rint values of 0.0283 and 0.0660, respectively, indicating good quality of crystals and investigated their ability against p38α 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 p38α MAPK suggest that during the course of 30 ns simulation run, compound Sulfo (I) attained stability, substantiating the consistency of its binding to p38α 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. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
| Item Type: | Journal Article |
|---|---|
| Publication: | Journal of Biomolecular Structure and Dynamics |
| Publisher: | Taylor and Francis Ltd. |
| Additional Information: | The copyright of this article belongs to Taylor and Francis Ltd |
| Department/Centre: | Division of Interdisciplinary Sciences > Computational and Data Sciences |
| Date Deposited: | 26 Feb 2021 05:54 |
| Last Modified: | 26 Feb 2021 05:54 |
| URI: | http://eprints.iisc.ac.in/id/eprint/68039 |
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