Principal component analysis on molecular descriptors as an alternative point of view in the search of new Hsp90 inhibitors

Inhibiting a protein that regulates multiple signal transduction pathways in cancer cells is an attractive goal for cancer therapy. Heat shock protein 90 (Hsp90) is one of the most promising molecular targets for such an approach. In fact, Hsp90 is a ubiquitous molecular chaperone protein that is involved in folding, activating and assembling of many key mediators of signal transduction, cellular growth, differentiation, stress-response and apoptothic pathways. With the aim to analyze which molecular descriptors have the higher importance in the binding interactions of these classes, we first performed molecular docking experiments on the 187 Hsp90 inhibitors included in the BindingDB, a pu…

Principal Component Analysis on molecular descriptors as alternative point of view in the search of new Hsp90 inhibitors

Inside the Hsp90 inhibitors binding mode through induced fit docking

Abstract During the last few decades, the development of new anticancer strategies had to face the instability of many tumors, occurring when the genetic plasticity of cells produces new drug-resistant cancers. It has been shown that a chaperone protein, heat shock protein 90 (Hsp90), is one of the fundamental factors involved in the cell response to stresses, and its role in many biochemical pathways has been demonstrated. Thus, the inhibition of Hsp90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. The natural antibiotic Geldanamycin is the first Hsp90 inhibitor that has been identified. Nevertheless, more potent and water-soluble sma…

Docking and synthesis of pyrrolopyrimidodiazepinone derivatives (PPDs) and their precursors: New scaffolds for DNA-interacting agents

New classes of pyrrolopyrimidodiazepinone derivatives (PPDs) and their precursors were studied in silico for their ability to form stable complex with DNA fragment. In the docking studies two binding modes can be envisaged: groove mode and intercalating mode. In the case of the best ligands the docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs whereas the side chain lies close to the minor groove. Synthetic approach to the PPD ring systems is discussed.

Molecular Docking and QSPR approach on NCI Anti-Cancer Agents Mechanism Database Topoisomerase I inhibitors

Molecular Docking approach on the Topoisomerase I inhibitors series included in the NCI anti-cancer agents mechanism database

Topoisomerase I (Top1) is an essential enzyme participating to all those processes associated with separation of DNA strands. It manages superhelical tensions through the transient breakage of one strand of duplex DNA, followed by the unwinding of supercoiled DNA. Camptothecins, a class of alkaloids extracted from the wood of a Chinese tree, were found to be potent inhibitors of Topoisomerase I. The National Cancer Institute (NCI) Anti-cancer Agents Mechanism Database contains several camptothecins derivatives, classified as selective Top1 inhibitors. In this work we performed molecular docking studies on 24 camptothecin-like inhibitors present in this database (using Autodock 3.0.5). In or…

LOOKING FOR NEW HSP-90 INHIBITORS THROUGH A MOLECULAR DOCKING/PHARMACOPHORE APPROACH

Investigation of flap motions in wild type and M46I/G51D Mutant HIV-1 Protease by molecular dynamics studies

Molecular Modeling and Dynamics of the transcriptionfactor NF-kB complexed with IkB

Targeted synthesis of pyrrolo tricycles for selective biomolecules overexpressed in cancer cells

BINDING MODES OF HSP90 INHIBITORS INVESTIGATED THROUGH INDUCED FIT DOCKING: IMPORTANCE OF ACTIVE SITE FLEXIBILITY

Protocollo chemiometrico per la predizione del meccanismo di azione di derivati a potenziale attività antitumorale

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 regula- tors, 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 vitr…

Identificazione e sintesi di nuovi potenziali inibitori di Heat Shock Protein 90

Multivariate Methods and Molecular Modeling Techniques in the study of Antitumor Agents

IKK-β inhibitors: An analysis of drug–receptor interaction by using Molecular Docking and Pharmacophore 3D-QSAR approaches

Abstract The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-β in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-β inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 in…

Molecular dynamics studies on HIV-1 protease: a comparison of the flap motions between wild type protease and the M46I/G51D double mutant

The emergence of drug-resistant mutants of HIV-1 is a tragic effect associated with conventional long-treatment therapies against acquired immunodeficiency syndrome. These mutations frequently involve the aspartic protease encoded by the virus; knowledge of the molecular mechanisms underlying the conformational changes of HIV-1 protease mutants may be useful in developing more effective and longer lasting treatment regimes. The flap regions of the protease are the target of a particular type of mutations occurring far from the active site. These mutations modify the affinity for both substrate and ligands, thus conferring resistance. In this work, molecular dynamics simulations were perform…

NCI Anti-cancer agent mechanism database. An analysis by the combined use of molecular docking and QSPR

Combined use of PCA and QSAR/QSPR to predict the drugs mechanism of action. An application to the NCI ACAM Database

During the years the National Cancer Institute (NCI) accumulated an enormous amount of information through the application of a complex protocol of drugs screening involving several tumor cell lines, grouped into panels according to the disease class. The Anti-cancer Agent Mechanism (ACAM) database is a set of 122 compounds with anti-cancer activity and a reasonably well known mechanism of action, for which are available drug screening data that measure their ability to inhibit growth of a panel of 60 human tumor lines, explicitly designed as a training set for neural network and multivariate analysis. The aim of this work is to adapt a methodology (previously developed for the analysis of …

PCA and QSAR/QSPR used in combination to predict the drugs mechanism of action. An application to the NCI ACAM Database

Molecular modelling and QSAR in the discovery of HIV-1 integrase inhibitors

The treatment regimens for the HIV-1 have mainly included reverse transcriptase or protease inhibitors but their long-term clinical utility is limited by severe side effects and viral drug resistance. A new attractive target for chemotherapeutic intervention can be the Integrase enzyme, that mediates the integration of HIV-1 DNA into a host chromosome, for which there is no known counterparts in the host cell. A number of derivatives have been found to inhibit IN in in vitro assays, but no successful drug based on them has emerged so far, although many compounds have been proposed. Moreover most of the inhibitors do not belong to a very precise structural class: this fact makes these compou…