Structural Dynamics of P-Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis.
Phosphatidylinositol 3,4,5-trisphosphate- (PIP3-) dependent Rac exchanger 1 (P-Rex1) functions as Rho guanine nucleotide exchange factor and is activated by synergistic activity of Gβγ and PIP3 of the heterotrimeric G protein. P-Rex1 activates Rac GTPases for regulating cell invasion and migration a...
| Publicado en: | BioMed Research International pp. 1 - 17 |
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| Autores principales: | , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Wiley-Blackwell
12/7/2023
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=174098714&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 174098714 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23146133 FT2T jtl: BioMed Research International issn: 23146133 maglogo: N pubinfo: dt: 12/7/2023 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 174098714 174098714 174098714 10.1155/2023/3882081 174098714 ppf: 1 ppct: 16 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Structural Dynamics of P-Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis. aug: au: Hameed, Alaa R. Ali, Sama Fakhri Alsallameh, Sarah M. S. Muhseen, Ziyad Tariq Almansour, Nahlah Makki ALSuhaymi, Naif Alsugoor, Mahdi H. Allemailem, Khaled S. affil: Department of Medical Laboratory Techniques, School of Life Sciences, Dijlah University College, Baghdad, Iraq sug: subj: Neoplasm Metastasis Drug Therapy Neoplasms Drug Therapy Proteins Metabolism Computer Simulation Antineoplastic Agents Therapeutic Use Human Male Chemistry, Physical Phospholipids Hydrolases Prostate Membrane Proteins Binding Sites Skin Neoplasms Enzymes Descriptive Statistics Comparative Studies Male ab: Phosphatidylinositol 3,4,5-trisphosphate- (PIP3-) dependent Rac exchanger 1 (P-Rex1) functions as Rho guanine nucleotide exchange factor and is activated by synergistic activity of Gβγ and PIP3 of the heterotrimeric G protein. P-Rex1 activates Rac GTPases for regulating cell invasion and migration and promotes metastasis in several human cancers including breast, prostate, and skin cancer. The protein is a promising therapeutic target because of its multifunction roles in human cancers. Herein, the present study attempts to identify selective P-Rex1 natural inhibitors by targeting PIP3-binding pocket using large-size multiple natural molecule libraries. Each library was filtered subsequently in FAF-Drugs4 based on Lipinski's rule of five (RO5), toxicity, and filter pan assay interference compounds (PAINS). The output hits were virtually screened at the PIP3-binding pocket through PyRx AutoDock Vina and cross-checked by GOLD. The best binders at the PIP3-binding pocket were prioritized using a comparative analysis of the docking scores. Top-ranked two compounds with high GOLD fitness score (>80) and lowest AutoDock binding energy (< -12.7 kcal/mol) were complexed and deciphered for molecular dynamics along with control-P-Rex1 complex to validate compound binding conformation and disclosed binding interaction pattern. Both the systems were seen in good equilibrium, and along the simulation time, the compounds are in strong contact with the P-Rex1 PIP3-binding site. Hydrogen bonding analysis towards simulation end identified the formation of 16 and 22 short- and long-distance hydrogen bonds with different percent of occupancy to the PIP3 residues for compound I and compound 2, respectively. Radial distribution function (RDF) analysis of the key hydrogen bonds between the compound and the PIP3 residues demonstrated a strong affinity of the compounds to the mentioned PIP3 pocket. Additionally, MMGB/PBSA energies were performed that confirmed the dominance of Van der Waals energy in complex formation along with favorable contribution from hydrogen bonding. These findings were also cross-validated by a more robust WaterSwap binding energy predictor, and the results are in good agreement with a strong binding affinity of the compounds for the protein. Lastly, the key contribution of residues in interaction with the compounds was understood by binding free energy decomposition and alanine scanning methods. In short, the results of this study suggest that P-Rex1 is a good druggable target to suppress cancer metastasis; therefore, the screened druglike molecules of this study need in vitro and in vivo anti-P-Rex1 validation and may serve as potent leads to fight cancer. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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