Computational Virtual Screening of Sulfonylurea chalcones as New Class of 5-Lipoxygenase Inhibitors by Molecular Docking Studies

Molecular docking study was performed on a series of 25 sulfonylureachalcones VS1-VS25 as potential 5-lipoxygenase (5-LO) inhibitors. The docking technique was applied to dock a set of representative compounds within the active site region of 3V99 (5-LO) using Molegro Virtual Docker v 4.0. For these compounds, the binding free energy (kcal/mol) was determined. The docking simulation clearly predicted the binding mode that is nearly similar to the crystallographic binding mode with 1.17A RMSD. Based on the validations and hydrogen bond interactions made by R substituents were considered for evaluation. The results avail to understand the type of interactions that occur between designed ligands with 3V99 binding site region and explain the importance of R substitution on sulfonylureachalcone basic nucleus.

[1]  Mechanism of action of adverse drug reactions: an overview. , 1997, Pharmacoepidemiology and drug safety.

[2]  T. Schmidt,et al.  Autoregulation of corticosteroid receptors. How, when, where, and why? , 1994, Receptor.

[3]  J. Mccammon,et al.  Accommodating Protein Flexibility in Computational Drug Design 1 , 2 , 2000 .

[4]  V. Avupati,et al.  De novo Based Ligand generation and Docking studies of PPARδ Agonists: Correlations between Predicted Biological activity vs. Biopharmaceutical Descriptors , 2010 .

[5]  R. Storn,et al.  Differential Evolution - A simple and efficient adaptive scheme for global optimization over continuous spaces , 2004 .

[6]  Schmidt Tj,et al.  Autoregulation of corticosteroid receptors. How, when, where, and why? , 1994 .

[7]  J A McCammon,et al.  Accommodating protein flexibility in computational drug design. , 2000, Molecular pharmacology.

[8]  V. Avupati,et al.  Synthesis, characterization and biological evaluation of some novel 2,4-thiazolidinediones as potential cytotoxic, antimicrobial and antihyperglycemic agents. , 2012, Bioorganic & medicinal chemistry letters.

[9]  Rainer Storn,et al.  Differential Evolution – A Simple and Efficient Heuristic for global Optimization over Continuous Spaces , 1997, J. Glob. Optim..

[10]  L. Bohlin,et al.  Flavan-3-ols Isolated from Some Medicinal Plants Inhibiting COX-1 and COX-2 Catalysed Prostaglandin Biosynthesis , 1998, Planta medica.

[11]  David B. Fogel,et al.  Docking Conformationally Flexible Small Molecules into a Protein Binding Site through Evolutionary Programming , 1995, Evolutionary Programming.

[12]  J. D. Elliott,et al.  Drug discovery in the next millennium. , 2000, Annual review of pharmacology and toxicology.

[13]  Larry L. Peterson,et al.  Reasoning about naming systems , 1993, TOPL.

[14]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[15]  C Y Ung,et al.  Computer automated prediction of potential therapeutic and toxicity protein targets of bioactive compounds from Chinese medicinal plants. , 2002, The American journal of Chinese medicine.

[16]  L Lasagna,et al.  New drug development in the United States from 1963 to 1992 , 1994, Clinical pharmacology and therapeutics.

[17]  O. Werz,et al.  Pharmacological intervention with 5-lipoxygenase: new insights and novel compounds , 2005 .

[18]  B. Shoichet,et al.  Flexible ligand docking using conformational ensembles , 1998, Protein science : a publication of the Protein Society.

[19]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules J. Am. Chem. Soc. 1995, 117, 5179−5197 , 1996 .

[20]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[21]  L Lasagna,et al.  New drug development in the United States from 1963 to 1990 , 1991, Clinical pharmacology and therapeutics.

[22]  I. Kuntz,et al.  Flexible ligand docking: A multistep strategy approach , 1999, Proteins.

[23]  J. Drews.  Drug discovery: a historical perspective. , 2000, Science.

[24]  G. N. Ramachandran,et al.  Conformation of polypeptides and proteins. , 1968, Advances in protein chemistry.

[25]  R Nussinov,et al.  Flexible docking allowing induced fit in proteins: Insights from an open to closed conformational isomers , 1998, Proteins.

[26]  Y. Z. Chen,et al.  Prediction of potential toxicity and side effect protein targets of a small molecule by a ligand-protein inverse docking approach. , 2001, Journal of molecular graphics & modelling.