TY - JOUR
T1 - Anti-inflammatory and anti-rheumatic potential of selective plant compounds by targeting TLR-4/AP-1 signaling
T2 - a comprehensive molecular docking and simulation approaches
AU - Khan, Ashrafullah
AU - Khan, Shafi Ullah
AU - Khan, Adnan
AU - Shal, Bushra
AU - Rehman, Sabih Ur
AU - Rehman, Shaheed Ur
AU - Htar, Thet Thet
AU - Khan, Salman
AU - Anwar, Sirajudheen
AU - Alafnan, Ahmed
AU - Rengasamy, Kannan RR
N1 - Funding Information:
Funding: This research was funded by the Scientific Research Deanship at the University of Hail, Saudi Arabia through project number RG-20069.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signal-ing, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydropho-bic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simu-lation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maxi-mum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.
AB - Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signal-ing, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydropho-bic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simu-lation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maxi-mum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.
KW - AP-1
KW - inflammation
KW - natural products
KW - NF-κB
KW - TLR-4
UR - http://www.scopus.com/inward/record.url?scp=85133444096&partnerID=8YFLogxK
U2 - 10.3390/molecules27134319
DO - 10.3390/molecules27134319
M3 - Article
C2 - 35807562
AN - SCOPUS:85133444096
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 13
M1 - 4319
ER -