Ligand‐Based Virtual Screening and Molecular Docking Studies to Identify the Critical Chemical Features of Potent Cathepsin D Inhibitors

Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; Lee, Keun Woo

doi:10.1111/j.1747-0285.2012.01339.x

Cited by 17 publications

(10 citation statements)

References 55 publications

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“… 63 Therefore, other approaches such as consensus scoring and/or a combination of multiple scoring functions are now utilized by researchers to avoid false-positive docking results. 64 …”

Section: Discussionmentioning

confidence: 99%

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

et al. 2020

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Cholinesterases (ChE) are well-known drug targets for the treatment of Alzheimer's disease (AD). In continuation of work to develop novel cholinesterase inhibitors, we utilized a structure-based scaffold repurposing approach and discovered six novel ChE inhibitors from our recently developed DNA gyrase inhibitor library. Among the identified hits, two compounds (denoted 3 and 18) were found to be the most potent inhibitor of acetylcholinesterase (AChE, IC 50 = 6.10 ± 1.01 μM) and butyrylcholinesterase (BuChE, IC 50 = 5.50 ± 0.007 μM), respectively. Compound 3 was responsible for the formation of H-bond and π−π stacking interactions within the active site of AChE. In contrast, compound 18 was well fitted in the choline-binding pocket and catalytic site of BuChE. Results obtained from in vitro cytotoxicity assays and in silico derived physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties indicate that repurposed scaffold 3 and 18 could be potential drug candidates for further development as novel ChE inhibitors.

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“… 63 Therefore, other approaches such as consensus scoring and/or a combination of multiple scoring functions are now utilized by researchers to avoid false-positive docking results. 64 …”

Section: Discussionmentioning

confidence: 99%

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

et al. 2020

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“…The enrichment factor (EF) determines the specificity and selectivity of the model to identify active compounds during the screening of decoy test set. The higher the EF value the higher will be the selectivity of the model [ [33] , [34] , [35] ].…”

Section: Methodsmentioning

confidence: 99%

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Zeb

Son

Yoon

et al. 2019

Computational and Structural Biotechnology Journal

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Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Å root mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of −122.18 kJ/mol and − 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.

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“…Molecular dynamic simulations of these structures were performed to improve the relaxation and orientation of the side chains. This procedure is usually crucial in molecular docking to reproduce the structural stability of the receptor in its native environment [63] . The software GROMACS 4.1.5 [64] , [65] was used to solvate the models in a cubic box with the chosen force field, and the solvent was treated explicitly (SPC water model).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Paracoccidioides lutzii Pb01 Isocitrate Lyase by the Natural Compound Argentilactone and Its Semi-Synthetic Derivatives

et al. 2014

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The dimorphic fungus Paracoccidioides spp. is responsible for paracoccidioidomycosis, the most prevalent systemic mycosis in Latin America, causing serious public health problems. Adequate treatment of mycotic infections is difficult, since fungi are eukaryotic organisms with a structure and metabolism similar to those of eukaryotic hosts. In this way, specific fungus targets have become important to search of new antifungal compound. The role of the glyoxylate cycle and its enzymes in microbial virulence has been reported in many fungal pathogens, including Paracoccidioides spp. Here, we show the action of argentilactone and its semi-synthetic derivative reduced argentilactone on recombinant and native isocitrate lyase from Paracoccidioides lutzii Pb01 (PbICL) in the presence of different carbon sources, acetate and glucose. Additionally, argentilactone and its semi-synthetic derivative reduced argentilactone exhibited relevant inhibitory activity against P. lutzii Pb01 yeast cells and dose-dependently influenced the transition from the mycelium to yeast phase. The other oxygenated derivatives tested, epoxy argentilactone and diol argentilactone-, did not show inhibitory action on the fungus. The results were supported by in silico experiments.

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Ligand‐Based Virtual Screening and Molecular Docking Studies to Identify the Critical Chemical Features of Potent Cathepsin D Inhibitors

Cited by 17 publications

References 55 publications

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

Inhibition of Paracoccidioides lutzii Pb01 Isocitrate Lyase by the Natural Compound Argentilactone and Its Semi-Synthetic Derivatives

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