Discovery of 2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitor

Nagarajan, Muthukaman; Deshmukh, Sanjay; Sarode, Neelam; Tondlekar, Shital; Tambe, Macchindra; Pisal, Dnyandeo; Shaikh, Mahamadhanif S.; Kattige, Vidya G.; Honnegowda, Srinivasa; Karande, Vikas; Kulkarni, Abhay; Jadhav, Satyawan B.; Mahat, Mahamad Yunnus A.; Gudi, Girish; Khairatkar-Joshi, Neelima; Gharat, Laxmikant A.

doi:10.1016/j.bmcl.2016.10.079

Cited by 8 publications

(1 citation statement)

References 47 publications

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“…Currently, Zaloglanstat (ISC-27864), an mPGES-1 inhibitor developed by Di Micco, S et al, which can be used to study asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain, and neurodegenerative diseases, has completed a Phase II clinical trial [ 31 ]. To date, researchers have discovered a range of mPGES-1 inhibitors with different chemical structures, such as MF63 antipyretic and analgesic effects of [2-(6-chloro-1 H -phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile] in an inflammatory animal model [ 32 ]; the effective and selective dioxane-fused mPGES-1 inhibitor tricyclic benz [d] imidazole derivatives [ 33 ], oxadiazole thione-benzimidazole derivatives [ 34 ], and PF-4693627, mPGES-1 inhibitors that can be used in studies of osteoarthritis and rheumatoid arthritis [ 35 ]; etc. The discovery of these inhibitors has enriched the selection and research of mPGES-1 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

mPGES-1 Inhibitor Discovery Based on Computer-Aided Screening: Pharmacophore Models, Molecular Docking, ADMET, and MD Simulations

et al. 2023

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mPGES-1 is an enzyme, which, when activated by inflammatory factors, can cause prostaglandin E synthesis. Traditional non-steroidal anti-inflammatory drugs are capable of inhibiting prostaglandin production, yet they can also cause gastrointestinal reactions and coagulation disorders. mPGES-1, the enzyme at the conclusion of prostaglandin production, does not cause any adverse reactions when inhibited. Numerous studies have demonstrated that mPGES-1 is more abundant in cancerous cells than in healthy cells, indicating that decreasing the expression of mPGES-1 could be a potential therapeutic strategy for cancer. Consequently, the invention of mPGES-1 inhibitors presents a fresh avenue for the treatment of inflammation and cancer. Incorporating a database of TCM compounds, we collected a batch of compounds that had an inhibitory effect on mPGES-1 and possessed IC50 value. Firstly, a pharmacophore model was constructed, and the TCM database was screened, and the compounds with score cut-off values of more than 1 were retained. Then, the compounds retained after being screened via the pharmacodynamic model were screened for docking at the mPGES-1 binding site, followed by high-throughput virtual screening [HTVS] and standard precision [SP] and super-precision [XP] docking, and the compounds in the top 20% of the XP docking score were selected to calculate the total free binding energy of MM-GBSA. The best ten compounds were chosen by comparing their score against the reference ligand 4U9 and the MM-GBSA_dG_Bind score. ADMET analysis resulted in the selection of ten compounds, three of which had desirable medicinal properties. Finally, the binding energy of the target protein mPGES-1 and the candidate ligand compound was analyzed using a 100 ns molecular dynamics simulation of the reference ligand 4U9 and three selected compounds. After a gradual screening study and analysis, we identified a structure that is superior to the reference ligand 4U9 in all aspects, namely compound 15643. Taken together, the results of this study reveal a structure that can be used to inhibit mPGES-1 compound 15643, thereby providing a new option for anti-inflammatory and anti-tumor drugs.

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