Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer’s disease

Jangid, Kailash; Devi, Bharti; Sahoo, Ashrulochan; Kumar, Vijay; Dwivedi, Ashish Ranjan; Thareja, Suresh; Kumar, Rajnish; Kumar, Vinod

doi:10.1080/07391102.2023.2201838

Cited by 6 publications

(5 citation statements)

References 64 publications

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“…Molecular dynamics simulation study is a crucial tool for the clear understanding of stability and conformational changes within the targeted protein–ligand complex. , VN-3 and VN-19 with balanced activity profiles against AChE and MAO-B were selected for the molecular dynamics simulation studies and performed the simulation of the docked complex of the compounds with both AChE and MAO-B, for the time-period of 100 ns. Figure depicts the root mean square deviation (RMSD) and radius of gyration (rGy) analysis from the MD trajectory of the protein–ligand complexes of VN-3 and VN-19 .…”

Section: Biological Resultsmentioning

confidence: 99%

“…Molecular dynamics simulation study is a crucial tool for the clear understanding of stability and conformational changes within the targeted protein−ligand complex. 33,34 VN-3 and VN-19 with balanced activity profiles against AChE and MAO-B were selected for the molecular dynamics simulation studies and performed the simulation of the docked complex of the 17B, and RMSD values of VN-3 and VN-19 with MAO-B also displayed stability throughout the simulation period, averaging at 0.2114 and 0.2188 nm, respectively. For the complexes of lead molecules with the respective proteins, i.e., AChE and MAO-B, RMSD values were found to be within the acceptable range suggesting that the protein and the ligand were stable throughout the timeperiod of MD simulation.…”

Section: Effect Of Vn-19 On Mda and Catalase Activity Inmentioning

confidence: 99%

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In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model

Kumar,

Jangid,

Kumar

et al. 2024

ACS Chem. Neurosci.

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Alzheimer’s disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer’s disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aβ1–42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ1–42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

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Section: Biological Resultsmentioning

confidence: 99%

Section: Effect Of Vn-19 On Mda and Catalase Activity Inmentioning

confidence: 99%

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model

Kumar,

Jangid,

Kumar

et al. 2024

ACS Chem. Neurosci.

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“…The most efficacious compound from docking studies was taken into MD simulation to study the interaction of protein and ligand for 100 ns via GROMACS 2021.6, carried out in the same way as previously reported by K. Jangid et al [27,49] . CHARMM36‐Mar2019 force field [50] was utilized to generate complex topology with the TIP3P model to solvate water box possessing dimension as a minimum of 1.5 nm distance from the surface of the protein.…”

Section: Computational Methodologymentioning

confidence: 99%

“…For analysis of the trajectory, GROMACS analytic tools, including RMSD (Root Mean Square Deviation), RMSF (Root Mean Square Fluctuation), rGy (Radius of Gyration), FEL (free energy landscape) and post‐FEL RMSD were computed [27] …”

Section: Computational Methodologymentioning

confidence: 99%

“…Since last few years we are working on the design, synthesis, and screening of small organic molecules as potential therapeutics for Alzheimer's Disease [26–29] . We got interested in the development of ligand‐based three‐dimensional (3D) pharmacophore(s) model against GSK‐3β which may assist in the identification of novel leads with improved activity [30] .…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Small‐Molecules as Potential GSK‐3β Inhibitors for the Treatment of Alzheimer's Disease Using Pharmacophore‐Based Virtual Screening

Jangid,

Devi,

Rani

et al. 2024

ChemistrySelect

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Glycogen synthase kinase‐3β (GSK‐3β) plays pivotal role in regulating diverse range of cellular functions. It plays negative role in cellular signaling pathways and believed to involved in the pathologies of various diseases like neurological disorders, type II diabetes, inflammation, cardiac hypertrophy, cancer and bipolar disorders. GSK‐3β is proposed as a promising target for drug discovery in treating these disease conditions. A number of structurally different chemical scaffolds including pyrimidinone derivatives have been identified as potential GSK‐3β inhibitors. In the current study, PHASE module of Schrödinger 3D QSAR was used on about 157 pyrimidinone derivatives for the development of statistically significant PLS model. Consecutively, the best pharmacophore hypothesis with features like three hydrogen bond acceptors (A1‐3), two hydrophobic regions (H1 and H2), and one aromatic ring (R1), was selected to screen ZINC and PUBCHEM databases. Molecules with matching pharmacophoric features and ROF were subjected to structure‐based virtual screening (HTVS→SP→XP) and MMGBSA. Two hits from each library were selected for MD simulation studies that showed good pharmacokinetic properties, binding score (−6.8–−8.8 kcal/mol) and ▵GMMGBSA (−55.80–−58.1 kcal/mol) as compared to the reference molecule, NP‐12. Similarly, MD simulation, and MMPBSA identified three compounds i. e. ZINC67743231, ZINC01582756, and PUBCHEM11553018 displaying stability in the binding pocket and demonstrated better binding affinity of −22.07, −27.33, and −30.61 kcal/mol, respectively, within the active site of GSK‐3β. DFT studies also demonstrated the stability of these three lead compounds with a high energy gap between HOMO and LUMO ranging between 0.14546 and 0.1718 eV.

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Identification of potential JNK3 inhibitors through virtual screening, molecular docking and molecular dynamics simulation as therapeutics for Alzheimer’s disease

Devi,

Jangid,

Kumar

et al. 2024

Mol Divers

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Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer’s disease

Cited by 6 publications

References 64 publications

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model

Discovery of Small‐Molecules as Potential GSK‐3β Inhibitors for the Treatment of Alzheimer's Disease Using Pharmacophore‐Based Virtual Screening

Identification of potential JNK3 inhibitors through virtual screening, molecular docking and molecular dynamics simulation as therapeutics for Alzheimer’s disease

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