Licia Pantano

Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53-MDM2 Interaction and its Inhibition by Small Molecules

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53-MDM2 interaction and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.

A3 adenosine receptor: homology modeling and 3D-QSAR studies.

Adenosine receptors (AR) belong to the superfamily of G-protein-coupled receptors (GPCRs). They are divided into four subtypes (A1, A2A, A2B, and A3) and can be distinguished on the basis of their distinct molecular structures, distinct tissues distribution, and selectivity for adenosine analogs. The hA3R, the most recently identified adenosine receptor, is involved in a variety of intracellular signaling pathways and physiological functions. Expression of hA3R was reported to be elevated in cancerous tissues and A3 antagonists could be proposed for therapeutic treatments of tumor. By using the crystal structure of hA2A adenosine receptor, recently published, we were able to obtain a model for A3R, further optimized using nanosecond scale molecular dynamics simulation. One hundred twenty two active and selective compounds were docked into this model and used as training set to generate pharmacophore models. These last address the prevalent features to be used for the search of new inhibitors. Therefore, it was employed as template to screen the ZINC database in the attempt to find new potent and selective human A3R antagonists. Our theoretical model of hA3 adenosine receptor was used to evaluate and quantify the structure-activity relationship of known antagonists. Moreover the obtained 3D-QSAR model allowed to identify new potential inhibitors.

Molecular Dynamics studies on Mdm2 complexes: an analysis of the inhibitor influence

p53 is a powerful anti-tumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors expresses wild-type p53, and its activation, by antagonizing its negative regulator Mdm2, might offer a new strategy for therapeutic protocol. In this work, we present a molecular dynamics study on Mdm2 structure bound to two different known inhibitors with the aim to investigate the structural transitions between apo-Mdm2 and Mdm2-inhibitor complexes. We tried to gain information about conformational changes binding a benzodiazepine derivative inhibitor with respect the known nutlin and the apo form. The conformational changes alter the size of the cleft and were mainly in the linker regions, suggesting that the overall dynamic nature of Mdm2 is related to dynamic movements in these regions.