Residue interaction networks of K-Ras protein with water molecules identifies the potential role of switch II and P-loop

Kumar, Sudhir; C, George Priya Doss

doi:10.1016/j.compbiomed.2021.104597

Cited by 6 publications

(5 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NMR S 2 calculated by Kumar et al with the DynaMine suggested that Q61H interferes with water molecule coordination and affects hydrolysis of GTP. 24 The results from MD simulations of Vatansever et al indicated that Q61H on the switch-II does not generate obvious influences on the fluctuations of the switch-II in active KRAS but evidently affects the flexibility of inactive protein. 40 Lu et al performed MD simulations on KRAS of multiple mutations and their studies verified that Q61H is more prone to alter the KRAS4B–GTP conformation to the active state than the G12C mutation.…”

Section: Introductionmentioning

confidence: 99%

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

et al. 2022

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The remaining hit molecules showed an average (~1–3) H‐bonds (Figure 6B). As the protein functions through cumulative atomic motions, the PCA 10,49–51 study was employed to understand the movements of the Cα atoms structurally for the five complexes. Based on the cumulative motion of the complexes, the first and last principal components were employed to construct the PCA graph.…”

Section: Resultsmentioning

confidence: 99%

“…8 Our previous study explored the importance of K-Ras binding site water molecules and dynamical changes of K-Ras mutant structures compared to the native model. 9,10 Another study focused on developing an engineered chimeric toxin, a pan-Ras biologic inhibitor for use in cancer therapy. 11 A recent study identified several FDA-approved inhibitors targeting G12C and G12D K-Ras models using pharmacophore modeling and a drug-repurpose approach.…”

Section: Introductionmentioning

confidence: 99%

“…The development of cmp4‐based drugs (pan‐Ras inhibitors) is promising for combination therapies and cetuximab in reducing tumor cell proliferation 8 . Our previous study explored the importance of K‐Ras binding site water molecules and dynamical changes of K‐Ras mutant structures compared to the native model 9,10 . Another study focused on developing an engineered chimeric toxin, a pan‐Ras biologic inhibitor for use in cancer therapy 11 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Tayubi

2022

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

The mutations at the hotspot region of K‐Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K‐Ras model with anti‐cancerous activity from food and drug administration (FDA)‐approved drug compounds. We implemented several computational strategies such as pharmacophore‐based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K‐Ras. We found that the FDA‐approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K‐Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h‐bonds, and potent inhibition against G13D K‐Ras. As a result, the current research identifies prospective K‐Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K‐Ras‐driven cancers.

show abstract

“…KRAS hyperactivation often results in sustained tumor proliferation, mostly common in lung, colorectal, and pancreatic carcinomas ( Friday and Adjei, 2005 ; Baines et al, 2011 ; Cox et al, 2014 ). Thus, researchers have identified small molecule inhibitors with anticancer activity to treat KRAS -driven cancers ( Kumar and Priya Doss, 2021a ; Kumar and Priya Doss, 2021b ; Udhaya Kumar et al, 2022 ).…”

Section: Types Of I-motifsmentioning

confidence: 99%

Emerging roles of i-motif in gene expression and disease treatment

et al. 2023

View full text Add to dashboard Cite

As non-canonical nucleic acid secondary structures consisting of cytosine-rich nucleic acids, i-motifs can form under certain conditions. Several i-motif sequences have been identified in the human genome and play important roles in biological regulatory functions. Due to their physicochemical properties, these i-motif structures have attracted attention and are new targets for drug development. Herein, we reviewed the characteristics and mechanisms of i-motifs located in gene promoters (including c-myc, Bcl-2, VEGF, and telomeres), summarized various small molecule ligands that interact with them, and the possible binding modes between ligands and i-motifs, and described their effects on gene expression. Furthermore, we discussed diseases closely associated with i-motifs. Among these, cancer is closely associated with i-motifs since i-motifs can form in some regions of most oncogenes. Finally, we introduced recent advances in the applications of i-motifs in multiple areas.

show abstract

Residue interaction networks of K-Ras protein with water molecules identifies the potential role of switch II and P-loop

Cited by 6 publications

References 61 publications

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Emerging roles of i-motif in gene expression and disease treatment

Contact Info

Product

Resources

About