Discovery of potential and selective COX-1 inhibitory leads using pharmacophore modelling, in silico screening and in vitro evaluation.

Cyclooxygenase -1 (COX-1) selective inhibitors are anticipated to be potential therapeutic agents for thrombosis, tumorigenesis, atherosclerosis, neuroprotection, and oxidative stress. In this study, a 3D-QSAR pharmacophore model was developed for potent and selective COX-1 inhibition based on 44 compounds from four different scaffolds using Phase, Schrödinger. One (hydrogen-bond) acceptor, one hydrophobic, and two aromatic sites (AHRR) contribute to COX-1 inhibitory activity. Test and decoy sets were used to corroborate the best hypothesis and the validated hypothesis was used to screen the SPECS database. The resultant hits were filtered by standard precision (SP) and extra precision (XP) modes of docking using Glide, Schrödinger which yielded five hits. Free energy calculations were carried out to quantify the affinity differences of the hits towards COX enzymes. These five hits were subjected to in vitro COX (ovine) inhibitory activity studies. The hits displayed potent COX-1 inhibitory activity and good selectivity versus COX-2 enzyme. The compounds also protected the nitric oxide (NO) induced cell death mediated by COX-1 in mouse macrophages cell line. Hence, we hypothesize that these compounds could be promising leads for the design of superior COX-1 inhibitors and insights gained from further exploration of the same could provide pertinent clues for the treatment of the conditions mentioned above.

[1]  M. Ramanathan,et al.  Synthesis, antimicrobial evaluation and QSAR studies of novel piperidin-4-yl-5-spiro-thiadiazoline derivatives. , 2010, Bioorganic & medicinal chemistry letters.

[2]  David E. Shaw,et al.  PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results , 2006, J. Comput. Aided Mol. Des..

[3]  Keun Woo Lee,et al.  Potent bace-1 inhibitor design using pharmacophore modeling, in silico screening and molecular docking studies , 2011, BMC Bioinformatics.

[4]  Cristiano Ruch Werneck Guimarães,et al.  MM-GB/SA Rescoring of Docking Poses in Structure-Based Lead Optimization , 2008, J. Chem. Inf. Model..

[5]  A. Tai,et al.  Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor. , 2008, Journal of medicinal chemistry.

[6]  M. Perretti,et al.  Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight. , 2003, Biochemical pharmacology.

[7]  R. Botting,et al.  Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition , 2004, Pharmacological Reviews.

[8]  Ying Yang,et al.  Design of novel N-phenylnicotinamides as selective cyclooxygenase-1 inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[9]  J. Irwin,et al.  Benchmarking sets for molecular docking. , 2006, Journal of medicinal chemistry.

[10]  C. Koboldt,et al.  Pharmacological analysis of cyclooxygenase-1 in inflammation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Loll,et al.  Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site. , 1996, Biochemistry.

[12]  V. Kulkarni,et al.  Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors , 2010, Molecular Diversity.

[13]  Walter Jaeger,et al.  'Bridged' stilbene derivatives as selective cyclooxygenase-1 inhibitors. , 2007, Bioorganic & medicinal chemistry.

[14]  S. Abramson,et al.  Nitric Oxide Synthase/COX Cross-Talk: Nitric Oxide Activates COX-1 But Inhibits COX-2-Derived Prostaglandin Production1 , 2000, The Journal of Immunology.

[15]  M. Perrone,et al.  Selective COX-1 inhibition: A therapeutic target to be reconsidered. , 2010, Current medicinal chemistry.

[16]  Hsuan-Liang Liu,et al.  The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies , 2011, Journal of Biomedical Science.

[17]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[18]  L. Marnett,et al.  Effects of nitric oxide and nitric oxide‐derived species on prostaglandin endoperoxide synthase and prostaglandin biosynthesis , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  Paul D Lyne,et al.  Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. , 2006, Journal of medicinal chemistry.

[20]  Yun Tang,et al.  Chemical function-based pharmacophore generation of selective κ-opioid receptor agonists by catalyst and phase , 2009, Journal of molecular modeling.

[21]  R. S. Rogers,et al.  3,4-diarylthiophenes are selective COX-2 inhibitors , 1995 .

[22]  Donald R. Miller,et al.  Protective effects of NSAIDs on the development of Alzheimer disease , 2008, Neurology.

[23]  A. Sacchetti,et al.  De Novo Synthesis of Cyclooxygenase-1 Counteracts the Suppression of Platelet Thromboxane Biosynthesis by Aspirin , 2006, Circulation research.

[24]  Alexander Golbraikh,et al.  Rational selection of training and test sets for the development of validated QSAR models , 2003, J. Comput. Aided Mol. Des..

[25]  L. Marnett,et al.  Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Gawaz,et al.  Contribution of cyclooxygenase-1 to thromboxane formation, platelet-vessel wall interactions and atherosclerosis in the ApoE null mouse. , 2009, Atherosclerosis.

[27]  Lawrence J Marnett,et al.  A Novel Mechanism of Cyclooxygenase-2 Inhibition Involving Interactions with Ser-530 and Tyr-385* , 2003, Journal of Biological Chemistry.

[28]  T. Lybrand,et al.  Stereoselective binding of indomethacin ethanolamide derivatives to cyclooxygenase-1. , 2005, Journal of medicinal chemistry.

[29]  M. Tutone,et al.  3D-QSAR pharmacophore modeling and in silico screening of new Bcl-xl inhibitors. , 2010, European journal of medicinal chemistry.

[30]  Cristiano Ruch Werneck Guimarães,et al.  Addressing Limitations with the MM-GB/SA Scoring Procedure using the WaterMap Method and Free Energy Perturbation Calculations , 2010, J. Chem. Inf. Model..

[31]  Hyung-Suk Kim,et al.  Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration , 1995, Cell.

[32]  J. Morrow,et al.  Cyclooxygenase-1 is a potential target for prevention and treatment of ovarian epithelial cancer. , 2005, Cancer research.

[33]  Anna L. Blobaum,et al.  Structural and Functional Basis of Cyclooxygenase Inhibition , 2007 .

[34]  P. Prasit,et al.  Synthesis and biological evaluation of 2,3-diarylthiophenes as selective Cox-2 and Cox-1 inhibitors , 1995 .

[35]  Ya-wen Wang,et al.  Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110α inhibitors , 2010, Journal of molecular modeling.

[36]  Yeon-Joo Kang,et al.  Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. , 2007, Progress in lipid research.

[37]  R. Kurumbail,et al.  Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents , 1996, Nature.

[38]  M. Ramanathan,et al.  Prediction of estrogen receptor β ligands potency and selectivity by docking and MM-GBSA scoring methods using three different scaffolds , 2012, Journal of enzyme inhibition and medicinal chemistry.

[39]  Luhua Lai,et al.  Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. , 2008, Journal of medicinal chemistry.

[40]  K. Takeuchi,et al.  Role of Cyclooxygenase (COX)-1 and COX-2 Inhibition in Nonsteroidal Anti-Inflammatory Drug-Induced Intestinal Damage in Rats: Relation to Various Pathogenic Events , 2002, Journal of Pharmacology and Experimental Therapeutics.

[41]  Hamed I. Ali,et al.  Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors. , 2007, Bioorganic & medicinal chemistry.

[42]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[43]  Rolf W Hartmann,et al.  Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy. , 2003, Journal of medicinal chemistry.