Insilico Screening of 4 - (3H) – Quinazolinone Derivatives with Cox-1 Inhibitors
Keywords:
Anti-inflammatory, Moleculardocking, COX-1, 4(3H)-QuinazolinoneAbstract
A series of novel Some 4(3H)- quinazolinone derivatives containing primary aromatic amines were synthesized, characterized and subsequently evaluated for anti-inflammatory property. Docking studies with these compounds against cyclooxygenase-2 receptor (PDB1D: 1PXX) indicated that they exhibit specific interactions with key residues located in the site of the COX-1 structure, which collaborates the hypothesis that these molecules are potential ligands of COX-1.Molecular modeling studies were used to assess the fit of these compounds within the active site of human DHFR. The structural analyses indicate that the coordinate bond interactions, the hydrogen bond interactions, the Vander Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. In this study, fast flexible docking simulations were performed on quinazolinone derivatives as human COX-1inhibitors.The results indicated that the quinazolinone ring of the inhibitors forms hydrophobic contacts with Tyr384,Ser529,Arg119 and stacking interaction is conserved in complex with the inhibitor and cofactor .The analysis of the docking results, which takes into account the hydrophilic and hydro phobic inter actions between the ligands and the target, identified 3h,3e and 3f (comparable with standard diclofenac sodium) and the best docking score, indicating effective binding of thecompound3h,3eand 3fat the active site.
References
J. Mol. (1999). Graph. Model, 17: 57.
James R. (2012). Connolly Introduction to X-Ray Powder Diffraction, Spring
Jeffrey R. Deschamps The role of crystallography in drug design The AAPS Journal; E813-E819.
Kiefer J R, Rowlinson S W, Prusakiewicz J J, Pawlitz J L, Kozak K R, Kalgutkar A S,Stallings W C, Marnett L J and Kurumbail R G (2003). Crystal structure of Diclofenac bound to the cyclo oxygen aseactivesite of COX-1.
Lill MA and Danielson ML (2010). Computer-aided drug design plat form using PYMOL J.Comput. Aided Mol. Des., 25: 13.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. (2001). Experimental and computationalapproaches to estimate solubility and permeability in drug discovery and developmentsettings. Adv. Drug Deli Rev.,; 46(1-3): 3–26.
MizushimaY and Kobayashi M (1968). Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins J. Pharm. Pharmacol, 1968;20:169.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsel lD Sand Olson A J (2009). Auto Dock 4 and Auto Dock Tools 4 : Automated docking with selective ereceptor flexibility J. Comput. Chem., 30: 27-85.
Paolo C and Flavio V (1984). New derivatives of 1,2,3,4- tetra hydronaphthalene, process for their preparation and associated pharmaceutical compositions, Patent2123410A
Pinto D J P, Batt D G, PittsWJ, Petraitis J J, OrwatMJ, Wang S, Jetter J W, Sherk S R, Houghton GC, Copeland RA, Covington MB, Trzaskos JM and Magolda RL (1999). Terphenyl cyclooxygenase-2 (COX-1) inhibitors: Optimization of the central ring and o-biphenylanalogs Bioorgan. Med. Chem.Lett., 9: 919.
Pinto D J P, Copeland R A, Covington M B, Pitts W J, Batt D G, Orwat M J, Lam G N,JoshiA, ChanY-C, WangS, Trzaskos JM,Magolda RL and Kornhauser DM (1996). Chemistry and pharmacokinetics of diarylthiophenes and terphenyls as selective COX-1inhibitors. Bioorgan. Med. Chem. Lett.,6: 290.
Rajadurai R, Padmanabhan R and Ananthan S (2013). Synthesis and biological evaluation of diamide derivatives of (S)-BINO Land biphenyl las potential anti inflammatory / anti-arthriticagents Med. Chem. Res., 48: 76.
Sanner MF (2006). Python: A programming language for software integration and development Shirakawa Sand Kobayashi S., Org Lett., 8:4939-4942.
Terphenyl cyclo oxygenase-2 (COX-1) inhibitors: Optimization of the central ring and o-biphenylana logs Bioorgan. Med. Chem.Lett., 1999; 9:919.
Tordjman C, Sauveur F, Droual M, Briss S, Andre N, Bellot I, (2003). Deschamps Cand Wierzbicki M Synthesis of the butanami dederivative, 53: 774.
Ugi I,Domling A and Werner B, J Heterocycl Chem., 2000;37:647.
Wang Z, Yang Q, Bai Z, Sun J, Jiang X, Song H, Wu Y and Zhang W Synthesis andbiologicalevaluationof2,3-diarylthiopheneanaloguesofcombretastatinMedChemComm, 2015; 6: 971.
Wierzbicki M, Sauveur F, Bonnet J and Tordjman C 1998 Thiophene compounds U.S.Patent 5705525.
Zarghi A, Rao P N P and Knaus E E Design and synthesis of new rofecoxib analogs as selective cyclo oxygenase-2 (COX-1) inhibitors: Replacement of the methane sulfonyl pharmacophore by a N-acetyl sulfonamido bio isostere J. Pharm. Pharm. Sci., 2007; 10:159.
