High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach
Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product...
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MDPI AG
2021-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/9/937 |
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doaj-15e57cec86df4ebeb9d6ed9a5458b9102021-09-26T00:55:58ZengMDPI AGPharmaceuticals1424-82472021-09-011493793710.3390/ph14090937High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget ApproachDanish Iqbal0Md Tabish Rehman1Abdulaziz Bin Dukhyil2Syed Mohd Danish Rizvi3Mohamed F. Al Ajmi4Bader Mohammed Alshehri5Saeed Banawas6M. Salman Khan7Wael Alturaiki8Mohammed Alsaweed9Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaDepartment of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi ArabiaDepartment of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaClinical Biochemistry & Natural Product Research Laboratory, Department of Biosciences, Integral University, Lucknow 226026, IndiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi ArabiaAlzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔG<sub>vdW</sub>) and non-polar solvation or lipophilic energy (ΔG<sub>Sol_Lipo</sub>) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.https://www.mdpi.com/1424-8247/14/9/937Alzheimer’s diseasemultitargetmolecular dynamics simulationsnatural-like compoundsvirtual screening |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Danish Iqbal Md Tabish Rehman Abdulaziz Bin Dukhyil Syed Mohd Danish Rizvi Mohamed F. Al Ajmi Bader Mohammed Alshehri Saeed Banawas M. Salman Khan Wael Alturaiki Mohammed Alsaweed |
| spellingShingle |
Danish Iqbal Md Tabish Rehman Abdulaziz Bin Dukhyil Syed Mohd Danish Rizvi Mohamed F. Al Ajmi Bader Mohammed Alshehri Saeed Banawas M. Salman Khan Wael Alturaiki Mohammed Alsaweed High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach Pharmaceuticals Alzheimer’s disease multitarget molecular dynamics simulations natural-like compounds virtual screening |
| author_facet |
Danish Iqbal Md Tabish Rehman Abdulaziz Bin Dukhyil Syed Mohd Danish Rizvi Mohamed F. Al Ajmi Bader Mohammed Alshehri Saeed Banawas M. Salman Khan Wael Alturaiki Mohammed Alsaweed |
| author_sort |
Danish Iqbal |
| title |
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach |
| title_short |
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach |
| title_full |
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach |
| title_fullStr |
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach |
| title_full_unstemmed |
High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach |
| title_sort |
high-throughput screening and molecular dynamics simulation of natural product-like compounds against alzheimer’s disease through multitarget approach |
| publisher |
MDPI AG |
| series |
Pharmaceuticals |
| issn |
1424-8247 |
| publishDate |
2021-09-01 |
| description |
Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔG<sub>vdW</sub>) and non-polar solvation or lipophilic energy (ΔG<sub>Sol_Lipo</sub>) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems. |
| topic |
Alzheimer’s disease multitarget molecular dynamics simulations natural-like compounds virtual screening |
| url |
https://www.mdpi.com/1424-8247/14/9/937 |
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