<i>In silico</i>hit optimization toward AKT inhibition: fragment-based approach, molecular docking and molecular dynamics study

Sanabria-Chanaga, Elkin Eduardo; Betancourt-Conde, Irene; Hernández‐Campos, Alicia; Téllez‐Valencia, Alfredo; Castillo, Rafael

doi:10.1080/07391102.2018.1546618

Cited by 14 publications

(5 citation statements)

References 40 publications

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“…During the 100ns MD simulation, an analysis of the RMSD, RMSF, and protein-ligand interaction was constructed to assess the domain correlations. Following the MD run, 1000 frames were created for each MD trajectory at 100ps intervals to study the binding kinetics of protein-ligand interaction 30, 31 . 38 .…”

Section: Methodsmentioning

confidence: 99%

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WITHDRAWN: Elucidating the molecular mechanism of phytochemicals against Parkinson’s disease through an integrated systems biology and molecular modeling approach

Bhowmik,

Kumar,

Manaithiya

et al. 2024

Preprint

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Traditional medicinal plants Mitragyna Speciosa and Plumbago Indica have exhibited several neuroprotective activities against Parkinson disease (PD) in several research studies. Nevertheless, further elucidation is needed about the molecular mechanism by which these medicinal plants exert their neuroprotective effects, as well as the relationship between their active constituents' structure and activity. Using a polypharmacology approach, the study identified metabolic pathways targeted by active phytochemicals of these medicinal plants. Extensive system biology approaches, including protein-protein interaction network analysis, KEGG pathway analysis, and gene functional enrichment study, pinpointed that AKT1 was the key gene involved in the molecular mechanism actions of the active phytochemicals concerning neuroprotective actions. A robust machine-learning guided bioactivity prediction model-based web application (https://akt1pred.streamlit.app/) against AKT1 was developed by implementing PubChem and Substructure fingerprint molecular signatures. Further validation of the model was done by conducting ROC and applicability domain analysis, with subsequent molecular docking studies to understand the molecular mechanisms of the phytochemicals. The web application predicted that delphinidin and kaempferol were the most active phytochemicals responsible for the neuroprotective effects of the medicinal plants, which was further supported by extensive molecular docking and molecular dynamics simulation study. These findings indicate a correlation between the structure of these compounds and their bioactivity, with some phytochemicals performing comparably or better than known FDA drugs. Results suggest significant potential for natural products in therapeutic applications, urging further in vitro and in vivo investigation and offering a robust foundation for future research into natural product-based small molecule binding and drug discovery in PD.

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Section: Methodsmentioning

confidence: 99%

“…Building a receptor grid around the co-crystallized ligand (Ipatasertib) of the enzyme enabled researchers to identify the binding site. Using the LigPrep module and the OPLS-2005 force field, the compounds were prepared for Glide docking 30,31,38 .…”

Section: Molecular Docking Studymentioning

confidence: 99%

WITHDRAWN: Elucidating the molecular mechanism of phytochemicals against Parkinson’s disease through an integrated systems biology and molecular modeling approach

Bhowmik,

Kumar,

Manaithiya

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…A crystal structure of CDK6 co‐crystallized with ligand (PDB code: 4EZ5) was used as a reference for superimposing CDK4 and identifying binding sites in the docking analysis of all three compounds. Subsequently, polar hydrogens and Kollman charges were added, and the numbers of rotatable bonds of the ligands were set using AutoDockTools (ADT) . One hundred docking cycles were performed with 500 000 evaluation steps using Genetic Algorithm.…”

Section: Methodsmentioning

confidence: 99%

Identification of Ligand‐binding Hotspot Residues of CDK4 Using Molecular Docking and Molecular Dynamics Simulation

Balasubramanian

Lee

Kim

2019

Bulletin Korean Chem Soc

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Cyclin‐dependent protein kinases (CDKs) are serine/threonine kinases of the CMGC family. The cyclin D/CDK4 complex plays an important role in cell proliferation. Deregulation of the CDK4‐cyclin D pathway leads to uncontrolled cell proliferation, causing various tumors and cancers in humans. CDK4 overexpression is widely observed in colorectal and uterine cervical carcinomas, liposarcomas, osteosarcomas, and breast cancer. CDK4 is extensively studied as a therapeutic target in breast cancer. Hence, the identification of the binding modes of inhibitors and important active‐site residues is crucial. However, an experimentally determined crystal structure of ligand‐bound CDK4 kinase has not been reported to date. Thus, this study aimed to identify hotspot residues in the ligand‐binding interface of CDK4. Three compounds exhibiting very high inhibitory activity against CDK4 (Cpd03, Cpd13, and Cpd14) were selected as potent antagonists in this study. Molecular docking and molecular dynamics simulation were carried out to identify the binding modes and crucial residues. For validation, we calculated total binding free energy and energy decomposition, which identified residues Ala151, Ala30, Asp152, His89, Ile9, Leu141, Phe87, Val17, and Val90 are the highest‐energy contributors important for inhibitor binding. The results of our study provide insights in the binding patterns of CDK4 inhibitors and reveal key residues in the ligand‐binding interface.

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“…Central anti-obesity targets in the PI3K-Akt signaling pathway include PI3K and AKT. For docking studies, obesity-inhibiting crystal structures of the PI3K-Akt pathway (PDB ID: 4FA6 and 4GV1) were obtained from the PDB for molecular docking studies [ 43 , 44 , 45 ]. Table 3 and Figure 16 show the structures resulting from the molecular docking of prosapogenin D to the two central anti-obesity targets of the PI3K-Akt signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Revealing Molecular Mechanisms of the Bioactive Saponins from Edible Root of Platycodon grandiflorum in Combating Obesity

Han,

Luo,

2024

Plants

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Obesity has emerged as a significant health concern, as it is a disease linked to metabolic disorders in the body and is characterized by the excessive accumulation of lipids. As a plant-derived food, Platycodon grandiflorum (PG) was reported by many studies, indicating that the saponins from PG can improve obesity effectively. However, the anti-obesity saponins from PG and its anti-obesity mechanisms have not been fully identified. This study identified the active saponins and their molecular targets for treating obesity. The TCMSP database was used to obtain information on 18 saponins in PG. The anti-obesity target of the PG saponins was 115 targets and 44 core targets. GO and KEGG analyses using 44 core anti-obesity genes and targets of PG-active saponins screened from GeneCards, OMIM, Drugbank, and DisGeNet showed that the PI3K-Akt pathway, the JAK-STAT pathway, and the MAPK pathway were the major pathways involved in the anti-obesity effects of PG saponins. BIOVIA Discovery Studio Visualizer and AutoDock Vina were used to perform molecular docking and process the molecular docking results. The molecular docking results showed that the active saponins of PG could bind to the major therapeutic obesity targets to play an obesity-inhibitory role. The results of this study laid the foundation for further research on the anti-obesity saponins in PG and their anti-obesity mechanism and provided a new direction for the development of functional plant-derived food. This research studied the molecular mechanism of PG saponins combating obesity through various signaling pathways, and prosapogenin D can be used to develop as a new potential anti-obesity drug.

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In silicohit optimization toward AKT inhibition: fragment-based approach, molecular docking and molecular dynamics study

Cited by 14 publications

References 40 publications

WITHDRAWN: Elucidating the molecular mechanism of phytochemicals against Parkinson’s disease through an integrated systems biology and molecular modeling approach

WITHDRAWN: Elucidating the molecular mechanism of phytochemicals against Parkinson’s disease through an integrated systems biology and molecular modeling approach

Identification of Ligand‐binding Hotspot Residues of CDK4 Using Molecular Docking and Molecular Dynamics Simulation

Revealing Molecular Mechanisms of the Bioactive Saponins from Edible Root of Platycodon grandiflorum in Combating Obesity

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