Chemical Biology & Drug Design

The interaction between MDM2 and p53 is a major target in anti-cancer drug design. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterised by NMR spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding-site and exploit the same sub-pockets used by p53, as well as nutlin and spirooxindole inhibitors.

Studies on compounds designed to degrade into a MEK and EGFR inhibitor + a DNA-directed species are described.

By a simplified approach small synthetic peptide libraries were screened to identify inhibitors of the complex between PED/PEA15 and D4α that is involved in molecular mechanisms of insulin resistance in type 2 diabetes. Small peptide sequences having H-donor groups and aromatic rings on specific positions are able to inhibit the complex and are promising scaffolds that could be converted into higher-affinity inhibitor compounds.

We conducted a comprehensive chemoinformatic analysis of combinatorial libraries obtained from “libraries from libraries”, a diversity-oriented synthesis (DOS) approach. It is demonstrated that libraries from libraries generates compounds truly diverse in both structural and property space. The approaches presented here are general and can be applied to assess the diversity of any other DOS library, or any other compound collection.

InChI-based optimal descriptors give more robust prediction for anti-HIV-1 activity (pEC50) than analogical descriptors calculated with SMILES.

CoMSIA study was carried out on a series of aryl alkanoic acid analogs as GPR40 agonists. CoMSIA contour maps were found to be complementary to the active site topology of GPR40 receptor model derived previously from site-directed mutagenesis and homology modeling techniques.

CCR3, a GPCR receptor plays a central role in allergic inflammation and is an important drug target for inflammatory diseases. Identification of active site residues by homology model assisted step-wise virtual screening will reveal its structure-based inhibitor design study.

The safety of Gd³⁺ complexes is evaluated by determining the acute toxicity or the long-term residual of Gd³⁺ in the body which depends primarily on the amount of free Gd³⁺ released by the dissociation of its complexes. The extent of dissociation depends on the selectivity of the ligand for Gd³⁺ over the endogenous metals (such as Zn²⁺) and on the kinetic stabilities of the complexes. The selectivity is determined, for example, as the ratio of the stability constants of the Gd³⁺ and Zn²⁺ complexes. If the rate of dissociation is much lower than the rate of excretion of the complex from the body (t_1/2=1.5 h), then the system is far from equilibrium and the extent of dissociation is determined by the inertness of the complex.

Lersivirine is a potent non-nucleoside reverse transcriptase inhibitor with exceptional mutant resilience. Here we compare the pharmacological and pharmacokinetic profile of lersivirine with its pyrazole and imidazole isomers.