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Inhibitor Selectivity (inhibitor + selectivity)
Selected AbstractsOn the Origins of Enzyme Inhibitor Selectivity and Promiscuity: A Case Study of Protein Kinase Binding to StaurosporineCHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2009Duangrudee Tanramluk Relationships between ligand binding and the shapes of the binding sites in families of homologous enzymes are investigated by comparing matrices of distances between key binding site atoms. Multiple linear regression is used to help identify key distances that influence ligand binding affinity. In order to illustrate the utility of this generic approach, we study protein kinase binding sites for ATP and the promiscuous competitive inhibitor, staurosporine. We show that the size of the gatekeeper residue and the closure between the first glycine of the GXGXXG motif and the aspartate of the DFG loop act together to promote tight binding. Our web-based tool, ,mapping analogous hetero-atoms onto residue interactions' (MAHORI), indicates that the greater the number of hydrogen bonds made by the kinase around the methylamine group of staurosporine, the tighter the binding. The conservation of surrounding atoms identified using our novel grid-based method clearly demonstrates that the most structurally conserved part of the binding site for staurosporine is the main chain of the hinge region. The critical role of interactions that are not dependent on side-chain identities is consistent with the promiscuous nature of this inhibitor. [source] The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivityFEBS JOURNAL, Issue 6 2001Vera Knäuper Interstitial collagen is degraded by members of the matrix metalloproteinase (MMP) family, including MMP-1. Previous work has shown that the region of MMP-1 coded for by exon 5 is implicated both in substrate specificity and inhibitor selectivity. We have constructed a chimeric enzyme, the exon 5 chimera, consisting primarily of MMP-1, with the region coded for by exon 5 replaced with the equivalent region of MMP-3, a noncollagenolytic MMP. Unlike MMP-3, the exon 5 chimera is capable of cleaving type I collagen, but the activity is only 2.2% of trypsin-activated MMP-1. ,Superactivation' of the chimera has no discernible effect, suggesting that the salt bridge formed in ,superactive' MMP-1 is not present. The kinetics for exon 5 chimera cleavage of two synthetic substrates display an MMP-3 phenotype, however, cleavage of gelatin is slightly impaired as compared to the parent enzymes. The Kiapp values for the exon 5 chimera complexed with synthetic inhibitors and N-terminal TIMP-2 also show a more MMP-3-like behaviour. However, the kon values for N-terminal TIMP-1 and N-terminal TIMP-2 are more comparable to those for MMP-1. These data show that the region of MMP-1 coded for by exon 5 is involved in both substrate specificity and inhibitor selectivity and the structural basis for our findings is discussed. [source] Can MM-PBSA calculations predict the specificities of protein kinase inhibitors?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2006Christopher S. Page Abstract An application of the Molecular mechanics Poisson,Boltzmann surface area (MM-PBSA) protocol to the prediction of protein kinase inhibitor selectivity is presented. Six different inhibitors are placed in equivalent orientations in each of six different receptors. Fully solvated molecular dynamics is then run for 1 ns on each of the 36 complexes, and the resulting trajectories scored, using the implicit solvent model. The results show some correlation with experimentally-determined specificities; anomalies may be attributed to a variety of causes, including difficulties in quantifying induced fit penalties and variabilities in normal modes calculations. Decomposing interaction energies on a per-residue basis yields more useful insights into the natures of the binding modes and suggests that the real value of such calculations lies in understanding interactions rather than outright prediction. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6MEDICINAL RESEARCH REVIEWS, Issue 3 2006Dmitri Pissarnitski Abstract The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure,activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs. © 2005 Wiley Periodicals, Inc. Med Res Rev [source] | ||||||||||