Quantitative Three Dimensional Structure Linear Interaction Energy Model of 5′-O-[N-(Salicyl)sulfamoyl]adenosine and the Aryl Acid Adenylating Enzyme MbtA
- 30 October 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (22), 7154-7160
- https://doi.org/10.1021/jm800668u
Abstract
MbtA (a salicyl AMP ligase) is a key target for the design of new antitubercular agents. On the basis of structure−activity relationship (SAR) data generated in our laboratory, a structure-based model is developed to predict the binding affinities of aryl acid−AMP bisubstrate inhibitors of MbtA. The approach described takes advantage of the linear interaction energy (LIE) technique to derive linear equations relating ligand structure to function. With only two parameters derived from molecular dynamics simulations, good correlation (R2 = 0.70) was achieved for a set of 31 inhibitors with binding affinities spanning 6 orders of magnitude. The results were applied to understand the effect of steric and heteroatom substitutions on bisubstrate ligand binding and to predict second generation inhibitors of MbtA. The resulting model was further validated by chemical synthesis of a novel inhibitor with a predicted LIE binding affinity of 1.6 nM and a subsequently determined experimental Kiapp of 0.7 nM.Keywords
This publication has 31 references indexed in Scilit:
- Inhibition of Siderophore Biosynthesis by 2-Triazole Substituted Analogues of 5′-O-[N-(Salicyl)sulfamoyl]adenosine: Antibacterial Nucleosides Effective against Mycobacterium tuberculosisJournal of Medicinal Chemistry, 2008
- Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure−Activity Relationships of the Nucleobase Domain of 5′-O-[N-(Salicyl)sulfamoyl]adenosineJournal of Medicinal Chemistry, 2008
- Ligand Binding to the Voltage-Gated Kv1.5 Potassium Channel in the Open State—Docking and Computer Simulations of a Homology ModelBiophysical Journal, 2008
- 5‘-O-[(N-Acyl)sulfamoyl]adenosines as Antitubercular Agents that Inhibit MbtA: An Adenylation Enzyme Required for Siderophore Biosynthesis of the MycobactinsJournal of Medicinal Chemistry, 2007
- QM/MM linear response method distinguishes ligand affinities for closely related metalloproteinsProteins-Structure Function and Bioinformatics, 2007
- A Mechanism-Based Aryl Carrier Protein/Thiolation Domain Affinity ProbeJournal of the American Chemical Society, 2007
- Antitubercular Nucleosides That Inhibit Siderophore Biosynthesis: SAR of the Glycosyl DomainJournal of Medicinal Chemistry, 2006
- Design, Synthesis, and Biological Evaluation of β-Ketosulfonamide Adenylation Inhibitors as Potential Antitubercular AgentsOrganic Letters, 2006
- Structure modeling, ligand binding, and binding affinity calculation (LR‐MM‐PBSA) of human heparanase for inhibition and drug designProteins-Structure Function and Bioinformatics, 2006
- Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesisThe FEBS Journal, 2005