Computational screening of promising beta-secretase 1 inhibitors through multi-step molecular docking and molecular dynamics simulations - pharmacoinformatics approach

dc.contributor.authorGupta, Shruti
dc.contributor.authorParihar, Devendra
dc.contributor.authorShah, Mokshada
dc.contributor.authorYadav, Shivali
dc.contributor.authorManagori, Husain
dc.contributor.authorBhowmick, Shovonlal
dc.contributor.authorPatil, Preeti Chunarkar
dc.contributor.authorAlissa, Siham A.
dc.contributor.authorWabaidur, Saikh Mohammad
dc.contributor.authorIslam, Md Ataul
dc.date.accessioned2020-05-25T06:03:08Z
dc.date.issued2020-04
dc.description.abstractAlzheimer’s disease (AD) is a neurodegenerative disorder generally developed with aging. AD slowly hammers the memory and cognitive abilities which eventually leads to abnormal behaviour, and ultimately left with disability and dependency. It is anticipated that by the year 2050, world population will experience the incidence of 100 million AD cases. It has been more than hundred years passed since AD recognized as a dreadfull disease, but there is no effective curative agent discovered against AD to date. One of the major hallmarks of the AD development is the accumulation of extracellular amyloid-beta (Aβ) plaques in the brain. In the amyloidogenic process, an extensively studied beta-secretase enzyme, known as BACE1, plays a key role in the accumulation and production of Aβ fragments. Therefore, successful inhibition of BACE1 by small molecular chemical entities can be an effective approach for anti-AD drug development. Hence, the current study has been perceived to find out potential BACE1 inhibitiors by virtual screening of entire Asinex chemical library database through multi-step molecular docking methodologies. Further, sequential screening of in-silico pharmacokinetics, molecular dynamic (MD) simulations analyses along with binding free energy estimation were performed. Comparative analyses and characteristics of molecular binding interactions assessment finally suggests that five molecules (B1–B5) to be the most promising BACE1 inhibitors. Molecular interactions analyses revealed that either one or both the catalytic dyad residues (Asp32 and Asp228) of BACE1 has formed strong molecular interactions with all the proposed molecules. Not only the catalytic dyad residues are involved in the formation of molecular binding interactions but also other important non-Asp binders residues such as Gly34, Tyr71, Trp115, Arg128, Lys224, Gly230, Thr231, Thr232, Arg235, Thr329, and Val332 found to interact with the selected compounds. Moreover, the dynamic behaviour of proposed molecules and BACE1 was explored through all-atoms MD simulation study for 100 ns time span. Analysis of MD simulation trajectories explained that all identified molecules are efficient enough to retain the structural and molecular interactions integrity inside the receptor cavity of BACE1 in dynamic environment. Finally, the binding free energy of each molecule has calculated from MD simulation trajectories through MM-PBSA method and found that all molecules possess a strong binding affinity towards the BACE1. The high negative binding free energies are found to be within the range of −994.978 to −561.562 kJ/mol for the identified compounds. Henceforth, analyses of extensively studied multi-cheminformatics approaches explained that proposed molecules might be promising BACE1 inhibitors for therapeutic application in AD, subjected to experimental validation.en_ZA
dc.description.departmentChemical Pathologyen_ZA
dc.description.embargo2021-04-05
dc.description.librarianhj2020en_ZA
dc.description.sponsorshipThe Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia through the Fast-track Research Funding Program.en_ZA
dc.description.urihttp://www.elsevier.com/ locate/molstrucen_ZA
dc.identifier.citationGupta, S., Parihar, D., Shah, M. et al. 2020, 'Computational screening of promising beta-secretase 1 inhibitors through multi-step molecular docking and molecular dynamics simulations - pharmacoinformatics approach', Journal of Molecular Structure, vol. 1205, art. 127660, pp. 1-13.en_ZA
dc.identifier.issn0022-2860 (print)
dc.identifier.issn1872-8014 (online)
dc.identifier.other10.1016/j.molstruc.2019.127660
dc.identifier.urihttp://hdl.handle.net/2263/74708
dc.language.isoenen_ZA
dc.publisherElsevieren_ZA
dc.rights© 2019 Published by Elsevier B.V. All rights reserved. Notice : this is the author’s version of a work that was accepted for publication in Journal of Molecular Structure. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. A definitive version was subsequently published in Journal of Molecular Structure, vol. 1205, art. 127660, pp. 1-13, doi : 10.1016/j.molstruc.2019.127660.en_ZA
dc.subjectAlzheimer’s disease (AD)en_ZA
dc.subjectBACE1en_ZA
dc.subjectVirtual screeningen_ZA
dc.subjectMolecular dockingen_ZA
dc.subjectMolecular dynamics simulationsen_ZA
dc.subjectBeta-secretase enzymeen_ZA
dc.titleComputational screening of promising beta-secretase 1 inhibitors through multi-step molecular docking and molecular dynamics simulations - pharmacoinformatics approachen_ZA
dc.typePostprint Articleen_ZA

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