In-silico assessment of novel peptidomimetics inhibitor targeting STAT3 and STAT4 N-terminal domain dimerization: A comprehensive study using molecular docking, molecular dynamics simulation, and binding free energy analysis

被引:1
作者
Shree, Megha [1 ,2 ]
Vaishnav, Jayanti [1 ]
Gurudayal
Ampapathi, Ravi Sankar [1 ,2 ]
机构
[1] CSIR Cent Drug Res Inst CDRI, Sophisticated Analyt Instrumentat Facil & Res SAIF, Lucknow 226031, India
[2] Acad Sci & Innovat Res, Ghaziabad 201002, Uttar Pradesh, India
关键词
JAK-STAT pathway; STAT3 & STAT4 proteins; Peptidomimetic foldamer; Molecular docking; Molecular dynamics simulation; PCA; MM/PBSA; Decomposition analysis; BETA-PEPTIDES; PREDICTION; INTERFACE; PROTEINS; GROMACS; PATHWAY; DISEASE; IMPACT; GROWTH; CHARMM;
D O I
10.1016/j.bbrc.2024.150584
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dysregulation in Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is closely linked to various cancer types. The N-terminal domain (NTD) of STAT proteins, upon dimerization, assumes a multifaceted role with remarkable adaptability in mediating interactions between proteins. Consequently, the strategic targeting of the N-terminal domain of STATs has emerged as a promising tactic for disrupting dimerization and impeding the translocation of STAT proteins. In this study, we have deployed an integrated in-silico methodology to rationally design Peptidomimetic foldamers as inhibitors of the N-terminal domains of STAT3 and STAT4, with the objective of disrupting protein dimerization. Consequently, we have judiciously designed a series of peptidomimetics that encompass beta(3)-amino acids, bearing side chains that mimic the residues within interface II of the dimeric structures of the NTDs. Employing molecular docking techniques; we have assessed the binding affinity of these designed peptidomimetics toward both the NTDs. Furthermore, we have conducted an evaluation of the stability and conformational alterations within the docked complexes over an extensive Molecular Dynamics, subsequently computing the binding free energy utilizing MM/PBSA calculations. Our findings unequivocally demonstrate that the peptidomimetic foldamers we have devised (Peptide-A, Peptide-B, and Peptide-C) exhibit a propensity to bind to and impede the dimerization process of the NTDs of both STAT3 and STAT4. These outcomes serve to underscore the potential of these meticulously designed peptidomimetics as potential candidates meriting further exploration in the realm of cancer prevention and management.
引用
收藏
页数:15
相关论文
共 82 条
  • [51] High STAT4 Expression Indicates Better Disease-free Survival in Patients with Gastric Cancer
    Nishi, Masaaki
    Batsaikhan, Bat-Erdene
    Yoshikawa, Kozo
    Higashijima, Jun
    Tokunaga, Takuya
    Takasu, Chie
    Kashihara, Hideya
    Ishikawa, Daichi
    Shimada, Mitsuo
    [J]. ANTICANCER RESEARCH, 2017, 37 (12) : 6723 - 6729
  • [52] The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention
    O'Shea, John J.
    Schwartz, Daniella M.
    Villarino, Alejandro V.
    Gadina, Massimo
    McInnes, Iain B.
    Laurence, Arian
    [J]. ANNUAL REVIEW OF MEDICINE, VOL 66, 2015, 66 : 311 - 328
  • [53] Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: The myoglobin case
    Papaleo, Elena
    Mereghetti, Paolo
    Fantucci, Piercarlo
    Grandori, Rita
    De Gioia, Luca
    [J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 2009, 27 (08) : 889 - 899
  • [54] UCSF chimera - A visualization system for exploratory research and analysis
    Pettersen, EF
    Goddard, TD
    Huang, CC
    Couch, GS
    Greenblatt, DM
    Meng, EC
    Ferrin, TE
    [J]. JOURNAL OF COMPUTATIONAL CHEMISTRY, 2004, 25 (13) : 1605 - 1612
  • [55] Toward β-amino acid proteins:: A cooperatively folded β-peptide quaternary structure
    Qiu, Jade X.
    Petersson, E. James
    Matthews, Erin E.
    Schepartz, Alanna
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (35) : 11338 - 11339
  • [56] In silico toxicology: computational methods for the prediction of chemical toxicity
    Raies, Arwa B.
    Bajic, Vladimir B.
    [J]. WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE, 2016, 6 (02) : 147 - 172
  • [57] 'Mixed' beta-peptides: A unique helical secondary structure in solution
    Seebach, D
    Gademann, K
    Schreiber, JV
    Matthews, JL
    Hintermann, T
    Jaun, B
    Oberer, L
    Hommel, U
    Widmer, H
    [J]. HELVETICA CHIMICA ACTA, 1997, 80 (07) : 2033 - 2038
  • [58] beta-peptides: a surprise at every turn
    Seebach, D
    Matthews, JL
    [J]. CHEMICAL COMMUNICATIONS, 1997, (21) : 2015 - 2022
  • [59] Modulation of STAT signaling by STAT-interacting proteins
    Shuai, K
    [J]. ONCOGENE, 2000, 19 (21) : 2638 - 2644
  • [60] Structure Based docking studies towards exploring potential anti-androgen activity of selected phytochemicals against Prostate Cancer
    Singh, Anshika N.
    Baruah, Meghna M.
    Sharma, Neeti
    [J]. SCIENTIFIC REPORTS, 2017, 7