Pharmacophore-based virtual screening, 3D QSAR, Docking, ADMET, and MD simulation studies: An in silico perspective for the identification of new potential HDAC3 inhibitors

Lanka, Goverdhan; Begum, Darakhshan; Banerjee, Suvankar; Adhikari, Nilanjan; P, Yogeeswari; Ghosh, Balaram

doi:10.1016/j.compbiomed.2023.107481

Cited by 29 publications

(4 citation statements)

References 91 publications

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“…These interactions play a critical role in maintaining the stability of the ligand-receptor complex and significantly influence the overall affinity for binding. The inclusion of aromatic ring characteristics in the pharmacophore model enables the prioritization of drugs that can engage in advantageous aromatic interactions, hence augmenting the probability of effective inhibition (23). Furthermore, the incorporation of donor and acceptor hydrogen bond characteristics into the pharmacophore model underscores the significance of these particular interactions in the establishment of stable complexes with the alpha-glucosidase enzyme (24).…”

Section: Discussionmentioning

confidence: 99%

Integrative computational approaches for designing novel alpha-glucosidase inhibitors based on curculigoside A derivatives: Virtual screening, molecular docking, and molecular dynamics

Asnawi,

Mieldianisa,

Aligita

et al. 2024

J Herbmed Pharmacol

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Introduction: Over 422 million people worldwide suffer from diabetes, causing 1.5 million fatalities annually. The existing medications have shortcomings, including poor glucose control and adverse effects. The present study aimed to create possible alpha-glucosidase inhibitors utilizing a curculigoside A derivative ligand-based model. Methods: A pharmacophore model was constructed utilizing the structure information of curculigoside A derivatives and PharmaGist. Subsequently, virtual screening, molecular docking, and molecular dynamics were employed to simulate the hits. Results: From six training sets, eleven pharmacophore models were developed; the model with the highest score (18.0435) was chosen for further analysis. Using the verified pharmacophore model, 270 547 chemicals from the ZINC natural product database were subjected to virtual screening. Subsequently, molecular docking was performed on the top 1000 hits with AutoDock Wizard from PyRx. This analysis unveiled 434 hits with better binding energies than acarbose, the native ligand. Subsequently, second optimal docking configurations were evaluated with AutoDock 2.4; this process yielded the discovery of three prospective inhibitors (ZINC000150350051, ZINC000008382292, and ZINC000085595291) characterized by the most advantageous binding energies. To evaluate the stability and dynamics of these ligand-receptor complexes, Gromacs 2022 molecular dynamics simulations were executed for one hundred nanoseconds. Out of the three hits, ZINC000085595291 (Hit03) exhibited good energy components and interaction stability constantly during the simulation. Conclusion: The integrated computational strategy identified promising alpha-glucosidase inhibitors in curculigoside A compounds, highlighting the potential of ZINC000085595291 (Hit03) as a potential diabetes therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Integrative computational approaches for designing novel alpha-glucosidase inhibitors based on curculigoside A derivatives: Virtual screening, molecular docking, and molecular dynamics

Asnawi,

Mieldianisa,

Aligita

et al. 2024

J Herbmed Pharmacol

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“…The step duration was 2 fs, and a coordinate file was saved every 75 ps for analysis. The analysis of the simulated data referred to the effective experience of predecessors. , The MD simulations for the 13 -DC II and 35 -DC II were performed with the help of the Desmond molecular dynamics simulation package of Schrodinger suite (Schrodinger Suite, 2023-2). The protein for the complexes was prepared using the Protein Preparation protocol from the Maestro v13.2 software of the Schrodinger suite (Schrodinger Suite, 2023-2).…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting β-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells

Zhu,

Liu,

et al. 2024

J. Med. Chem.

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Aberrant activation of the Wnt/β-catenin signaling is associated with tumor development, and blocking β-catenin/ BCL9 is a novel strategy for oncogenic Wnt/β-catenin signaling. Herein, we presented two novel β-catenin variations and exposed conformational dynamics in several β-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting β-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of β-catenin. Among them, 28 had a strong affinity for β-catenin (K d = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting β-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance.

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“…Finally, approximate 1000 frames were obtained and the stability of ligand-receptor complexes was assessed by calculating several important parameters such as Root Mean Square Deviation (RMSD), Root mean square uctuations (RMSF). Meanwhile, their interactions also were analysed when simulation jobs complete [20].…”

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates

Xu,

Yang,

Yang

et al. 2024

Preprint

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PHGDH has been identified as a promising drug target for the therapy/management of various cancers. 3D-QSAR pharmacophore model-based virtual screening, ADME/T prediction, molecular docking, lead optimization and molecular dynamics simulation were utilized to identify novel potential PHGDH inhibitors. A ligand-based 3D-QSAR pharmacophore model was developed using HypoGen algorithm methodology of Discovery Studio. The selected Hypo_2 pharmacophore model was further validated by test set validation, cost analysis, Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. Estimated activity, drug-likeness, molecular docking, growing scaffold and molecular dynamics simulation were applied in combination in order to further narrow the number of virtual hits. Finally, an all-in-one combination was employed successfully to design and develop two potential anti-cancer candidates.

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Pharmacophore-based virtual screening, 3D QSAR, Docking, ADMET, and MD simulation studies: An in silico perspective for the identification of new potential HDAC3 inhibitors

Cited by 29 publications

References 91 publications

Integrative computational approaches for designing novel alpha-glucosidase inhibitors based on curculigoside A derivatives: Virtual screening, molecular docking, and molecular dynamics

Integrative computational approaches for designing novel alpha-glucosidase inhibitors based on curculigoside A derivatives: Virtual screening, molecular docking, and molecular dynamics

Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting β-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates

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