Introduction

Type 2 diabetes is a component of a complex metabolic syndrome, characterized by abnormal insulin secretion caused by impaired P-cell function and insulin resistance in target tissues.1,2 It has emerged as one of the world's most debilitating diseases, and its prevalence is reaching epidemic proportions, with over 300 million cases expected worldwide by 2025.3 The patho-genesis of type 2 diabetes is complex and it is influenced by both genetic and environmental factors, including obesity and...

Ribosome mode of action

Ribosomes comprise two ribonucleoprotein subunits (Figure 1a) that associate to form the functional ribosome. While elongation proceeds, each subunit operates cooperatively. The small subunit provides the mRNA binding machinery (Figure 1b) and the path along which the mRNA progresses, the decoding center and the major component controlling translation fidelity. The large subunit performs the main ribosomal catalytic function, namely amino acid polymerization, and provides the protein exit...

Exploring the inhibitor binding site

Fyn Dfg Out

STRUCTURES OF ABL IN COMPLEX WITH DIFFERENT CHEMOTYPES An attractive strategy to overcome or avoid most cases of resistance, would be to administer two drugs in combination, which utilise different binding interactions to inhibit the Abl kinase. In particular, a useful combination could be a compound which binds to the inactive conformation, such as imatinib, with a compound which bound to an active conformation. Examples of chemotypes used as leads for targeting the active conformation...

How large is the contribution of a hydrogen bond to the strength of the proteinligand interaction

Trna Hydrogen Bond

Discussing protein-ligand interactions, the inherent question arises as to how large the contribution of a particular hydrogen bond to the binding affinity actually is. This question may be answered experimentally when two protein-ligand complexes are compared to each other that only differ from one another by one hydrogen bond. Such a comparison is possible, for example, by using protein mutants in which one single amino acid that forms an H-bond to the ligand is replaced by another residue...

Crystal structures molecular modeling and rational design

INITIAL MODELING WORK a-SERIES VERSUS p-SERIES Once the binding mode of both series was established, efforts were started to use the structural information available for the design of structurally novel and diverse inhibitors that would nevertheless retain potency and selectivity. As indicated in Fig. 5, comparison of the binding mode of a- and p-amino acid compounds suggested that the two classes had some shared functionality, in particular the presence of conserved hydrogen bond...

The binding constant Ki describes the strength of the proteinligand interaction

The binding of a ligand to its target protein can be measured. The Binding Constant Ki Eq. 1 may be regarded as a characteristic binding quantity. To be precise, it is a dissociation constant KD, and its reciprocal is the association constant KA. The inhibition constant Ki of enzymes is determined in an assay. Although they do not describe exactly the same, these values are generally used equivalently. In the following only the abbreviation K will be used. The binding constant describes the...