Insight into the Interaction of Cationic Porphyrin-Anthraquinone Hybrids with Hsp90: In Silico Analysis

Heat shock protein 90 (Hsp90) is responsible for the correct folding of many cellular proteins. Several Hsp90 inhibitors have been developed for cancer treatment. The present in silico study aimed to evaluate the potential of several porphyrin derivatives conjugated with anthraquinone groups as Hsp90 inhibitors by using simulation of molecular docking and molecular dynamics. The binding mode of porphyrin hybrids to Hsp90, which was examined by using AutoDock 4.2, showed that all six porphyrin compounds fit well in the binding pocket of Hsp90. The pi-cationic interactions with Lys58 were exclusively observed in the interaction of each porphyrin hybrid. Stabilities of porphyrin-Hsp90 complexes were confirmed by 40-ns MD simulation, which was carried out with the help of AMBER16. Prediction of ligand affinity by using the MM-PBSA method showed that all complexes were energetically favorable as indicated by a negative binding free energy. The predicted affinities of tris−H2PyP−AQ, tris−H2PzP−AQ, bis−H2PzP−AQ, and mono−H2PzP−AQ are better than those of geldanamycin, a known inhibitor of Hsp90, which shows the importance of the electrostatic and van der Waals energies for ligand binding

Phytochemical, in vitro and in silico analyses of hexanic alpinia galanga extract in cancer chemo-prevention study on breast cancer cells

Cancer is one of the major health concerns and leading causes of mortality worldwide. The major problem in the cancer chemotherapy is the drug-resistant of the established drugs. Therefore, the immediate search for anti-cancer agents from plant sources has been done intensively. The purpose of this study was to evaluate the anticancer effects of Alpinia galanga extracts against several breast cancer cell lines. The crude extracts were isolated via aqueous and different polarity of solvents such as hexane, acetone and ethanol using soxhlet extraction rotary evaporator. Cytotoxicity of crude extracts were screened by using MTT assay against normal human liver (WRL-68), and MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cell lines. Active crude extract with lowest IC50 value was selected for fractionated via column chromatography (CC) technique. Then, fractionates were re-evaluated for cytotoxicity profile and anti-migration activity. Further determination of active fraction induced cells death through cell cycle, apoptosis and pyroptosis was conducted flow cytometry and caspases bioluminescence studies. Their morphology structures were assessed under phase-contrast microscopy and inverted fluorescent-microscopy. Besides that, identification of bioactive molecules using gas chromatography-mass spectrophotometry (GC-MS) and prediction potential mechanism pathways was conducted through in silico molecular docking study. Active hexanic A. galanga extract with lowest IC50 value at 2.12 μg/mL and highest selectivity index (10.17) against MDA-MB-231 cells was fractionated. It was revealed that fraction F6-4 possessed potent anticancer and anti-migration activities. Interestingly, fraction F6-4 demonstrated both apoptosis and pyroptosis-induce cells death which involves ATP-dependent in MDA-MB-231 cells. The inhibition of MDA-MB-231 cells was characterized with apoptosis cells positive Annexin-V FITC due to exposure of phosphatidylserines (PS) on cell membrane after treatment and underwent cell cycle arrest at G0/G1 checkpoint. Further, the molecular mechanisms of inhibition of MDA-MB-231 cells by fraction F6-4 emphasizes on activation extrinsic and intrinsic caspases cascade, including inflammation caspase-1 (pyroptosis). Also, distinctly apoptosis and pyroptosis morphological changes were observed. Concomitantly, major bioactive compound was identified in both hexanic A. galanga and fraction F6-4 is 4-Chromanol. In silico molecular docking elucidated that 4-Chromanol induced apoptosis mechanisms through interaction between molecular extrinsic and intrinsic pathways, and also reveals as strong competitive inhibitor against Cdk2 and Cdk6. In conclusion, 4-Chromanol exhibited potent anticancer against triple negative breast cancer (TNBC) subtype and elucidate possible underlying mechanism(s) of apoptosis pathways

Anticancer Properties of Natural and Derivative Products

Natural products are bioactive compounds synthesized by terrestrial and marine plants, microorganisms and animals, whose main objective is to prevent them from attacks by predators and/or pathogens. Traditionally since ancient times, different cultures have used these compounds for the prevention and treatment of various human diseases. During the last few years, it has been reported that most of these phytochemicals possess a variety of interesting and significant biological properties, such as analgesic, antiallodynic, antidiabetic, antioxidant, antiparasitic, antimicrobial, antiviral, antiatherogenic, anti-inflammatory, antiproliferative, antitumor and normal growth stimulants, as well as significant cardioprotective and neuroprotective activity. This thematic book aims to collect and disseminate some of the most significant and recent contributions of the use of the natural compounds called phytochemicals, as well as some of their chemical derivatives, for the prevention and treatment of cancer and other accompanying diseases. On the other hand, in recent years, the synthesis of numerous chemical derivatives of these natural compounds has also intensified, with the aim of enhancing their bioactive capacities. Among all these bioactivities, special attention has been paid to its antitumor capacity through the potential modulation of cancer initiation and growth, cell differentiation, apoptosis and autophagy, angiogenesis, and metastatic dissemination. In addition, a considerable number of studies have linked their anticancer effects to their anti-inflammatory and antioxidant activities

A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA

This Special Issue of the International Journal of Molecular Science comprises a comprehensive study on “Metal Complex Interactions with Nucleic Acids and/or DNA”. This Special Issue has been inspired by the important contribution of Prof. Nick Hadjiliadis to the field of palladium or/and platinum/nucleic acid interactions. It covers a selection of recent research and review articles in the field of metal complex interactions with nucleic acids and/or DNA. Moreover, this Special Issue on "Metal Complexes Interactions with Nucleic Acids and/or DNA" provides an overview of this increasingly diverse field, presenting recent developments and the latest research with particular emphasis on metal-based drugs and metal ion toxicity

Novel Anti-cancer Agents and Cellular Targets and Their Mechanism(s) of Action

Patient outcomes remain poor for many cancers despite improvements in treatments and new molecular-targeted biomedicines for certain cancer types or subtypes. Dose-limiting toxicity, a narrow therapeutic index, and the development of resistance to traditional anti-cancer agents are well-established. It is apparent that inherent and acquired drug resistance are major challenges with molecular-targeted agents and that on- as well as off-target side effects can still occur. Other issues include drug metabolism by the body and safely supplying a sufficient amount of active drug to the tumor cells. There is a clear and urgent need for new molecular targets and drugs that specifically target cancer cells in different ways to existing approved drugs. This book, through a collection of eight research articles and two review articles from the Biomedicines themed Special Issue ‘Novel Anti-Cancer Agents and Cellular Targets and Their Mechanism(s) of Action’, provides a snapshot of some of the diverse and exciting research approaches being taken by the cancer research community in trying to address some of these therapeutic challenges