			Home About us Contact

Inhibitor Bound (inhibitor + bound)

Distribution by Scientific Domains

Chemistry	100%

Selected Abstracts

Calculation of relative binding affinities of fructose 1,6-bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2007
Ravichandra Mutyala
Abstract The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: 113Tyr , 113Phe, 31Thr , 31Ala, 31Thr , 31Ser, 177Met , 177Ala, and 30Leu , 30Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: 113Tyr and 31Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source]

Progress in type II dehydroquinase inhibitors: From concept to practice

MEDICINAL RESEARCH REVIEWS, Issue 2 2007
Concepción González-Bello
Abstract Scientists are concerned by an ever-increasing rise in bacterial resistance to antibiotics, particularly in diseases such as malaria, toxoplasmosis, tuberculosis, and pneumonia, where the currently used therapies become progressively less efficient. It is therefore necessary to develop new, safe, and more efficient antibiotics. Recently, the existence of the shikimic acid pathway has been demonstrated in certain parasites such as the malaria parasite. These types of parasites cause more than a million casualties per year, and their effects are particularly strong in people with a compromised immune system such as HIV patients. In such cases it is possible that inhibitors of this pathway could be active against a large variety of microorganisms responsible for the more opportunistic infections in HIV patients. Interest in this pathway has resulted in the development of a wide variety of inhibitors for the enzymes involved. This review covers recent progress made in the development of inhibitors of the third enzyme of this pathway, i.e., the type II dehydroquinase. The X-ray crystal structures of several dehydroquinases (Streptomyces coelicolor, Mycobacterium tuberculosis, etc.) with an inhibitor bound in the active site have recently been solved. These complexes identified a number of key interactions involved in inhibitor binding and have shed light on several aspects of the catalytic mechanism. These crystal structures have also proven to be a useful tool for the design of potent and selective enzyme inhibitors, a feature that will also be discussed. © 2006 Wiley Periodicals, Inc. Med Res Rev [source]

High-resolution structure of human phosphoserine phosphatase in open conformation

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2003
Yves Peeraer
The crystal structure of human phosphoserine phosphatase (HPSP) in the open conformation has been determined at a resolution of 1.53,Å. The crystals are orthorhombic, belonging to space group C2221, with unit-cell parameters a = 49.03, b = 130.25, c = 157.29,Å. The asymmetric unit contains two molecules. Phase information was derived from a multiwavelength anomalous dispersion (MAD) experiment conducted at three wavelengths using a selenomethionine-derivative crystal of HPSP. The structure was refined using CNS to a final crystallographic R value of 21.6% (Rfree = 23.4%). HPSP is a dimeric enzyme responsible for the third and final step of the l -serine biosynthesis pathway. It catalyses the Mg2+ -dependent hydrolysis of l -phosphoserine. Recently, the structure of HPSP in complex with an inhibitor bound to the active site has been reported to be the open conformation of the enzyme. Here, the structure of HPSP is reported in the absence of substrate in the active site. Evidence is presented that HPSP in an uncomplexed form is in an even more open conformation than in the inhibitor complex. In this state, the enzyme is partially unfolded to allow the substrate to enter the active site. Binding of the substrate causes HPSP to shift to the closed conformation by stabilizing the partially unfolded region. In the present structure a Ca2+ ion is bound to the active site and an explanation is given why HPSP is not active when in the active site Mg2+ is replaced by a Ca2+ ion. [source]

A micromolar O-sulfated thiohydroximate inhibitor bound to plant myrosinase

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 2 2010
Arthur Besle
The 1.6,Å resolution structure of the micromolar competitive inhibitor S -(N,N -dimethylaminoethyl) phenylacetothiohydroximate- O -sulfate bound to Sinapis alba myrosinase, a plant thioglucosidase, is reported. Myrosinase and its substrates, the glucosinolates, are part of the plant's defence system. The sulfate group and the phenyl group of the inhibitor bind to the aglycon-binding site of the enzyme, whereas the N,N -dimethyl group binds to the glucose-binding site and explains the large improvement in binding affinity compared with previous compounds. The structure suggests ways to increase the potency and specificity of the compound by improving the interactions with the hydrophobic pocket of the aglycon-binding site. [source]