PMID- 35807562 OWN - NLM STAT- MEDLINE DCOM- 20220712 LR - 20220716 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 27 IP - 13 DP - 2022 Jul 5 TI - Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches. LID - 10.3390/molecules27134319 [doi] LID - 4319 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 kappaappa B (NF-kappaB) 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 signaling, 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-kappaB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic 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-kappaB 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 simulation, 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 maximum 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. FAU - Khan, Ashrafullah AU - Khan A AD - Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. AD - Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar 25000, Pakistan. FAU - Khan, Shafi Ullah AU - Khan SU AD - Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar 25000, Pakistan. AD - Product & Process Innovation Department, Qarshi Brands (Pvt) Ltd., Hattar 22610, Pakistan. FAU - Khan, Adnan AU - Khan A AUID- ORCID: 0000-0001-7950-2983 AD - Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. FAU - Shal, Bushra AU - Shal B AD - Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. AD - Faculty of Health Sciences, IQRA University, Islamabad Campus (Chak Shahzad), Park link Rd., Islamabad 44000, Pakistan. FAU - Rehman, Sabih Ur AU - Rehman SU AUID- ORCID: 0000-0002-0880-0358 AD - Department of Pharmacy, Forman Christian College (A Chartered University), Lahore 54600, Pakistan. FAU - Rehman, Shaheed Ur AU - Rehman SU AUID- ORCID: 0000-0002-5185-065X AD - Department of Pharmacy, Forman Christian College (A Chartered University), Lahore 54600, Pakistan. FAU - Htar, Thet Thet AU - Htar TT AUID- ORCID: 0000-0001-6193-1237 AD - School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia. FAU - Khan, Salman AU - Khan S AUID- ORCID: 0000-0002-6226-8470 AD - Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. FAU - Anwar, Sirajudheen AU - Anwar S AUID- ORCID: 0000-0002-0926-2790 AD - Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 55211, Saudi Arabia. FAU - Alafnan, Ahmed AU - Alafnan A AUID- ORCID: 0000-0001-7883-1021 AD - Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 55211, Saudi Arabia. FAU - Rengasamy, Kannan Rr AU - Rengasamy KR AD - Center of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. AD - Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha Dental College, Chennai 600077, India. LA - eng PT - Journal Article DEP - 20220705 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Anti-Inflammatory Agents) RN - 0 (NF-kappa B) RN - 0 (Toll-Like Receptor 4) RN - 0 (Transcription Factor AP-1) RN - 5G06TVY3R7 (Rutin) SB - IM MH - Anti-Inflammatory Agents/pharmacology/therapeutic use MH - Humans MH - Inflammation/drug therapy MH - Molecular Docking Simulation MH - Molecular Dynamics Simulation MH - NF-kappa B/metabolism MH - Rutin/pharmacology MH - Signal Transduction MH - *Toll-Like Receptor 4 MH - *Transcription Factor AP-1/metabolism PMC - PMC9268648 OTO - NOTNLM OT - AP-1 OT - NF-kappaB OT - TLR-4 OT - inflammation OT - natural products COIS- The authors declare no conflict of interest. EDAT- 2022/07/10 06:00 MHDA- 2022/07/14 06:00 PMCR- 2022/07/05 CRDT- 2022/07/09 01:20 PHST- 2022/05/11 00:00 [received] PHST- 2022/06/23 00:00 [revised] PHST- 2022/06/29 00:00 [accepted] PHST- 2022/07/09 01:20 [entrez] PHST- 2022/07/10 06:00 [pubmed] PHST- 2022/07/14 06:00 [medline] PHST- 2022/07/05 00:00 [pmc-release] AID - molecules27134319 [pii] AID - molecules-27-04319 [pii] AID - 10.3390/molecules27134319 [doi] PST - epublish SO - Molecules. 2022 Jul 5;27(13):4319. doi: 10.3390/molecules27134319.