Current Medicinal Chemistry - Volume 24, Issue 39, 2017

Background: Olive oil and table olive biophenols have been shown to significantly enrich the hedonic-sensory and nutritional quality of the Mediterranean diet. Oleuropein is one of the predominant biophenols in green olives and leaves, which not only has noteworthy freeradical quenching activity but also putatively reduces the incidence of various cancers. Clinical trials suggest that the consumption of extra virgin olive oil reduces the risk of several degenerative diseases. The oleuropein-based bioactives in olive oil could reduce tumor necrosis factor α, interleukin-1β and nitric oxide. Therefore, the quality of olive biophenols should be preserved and even improved due to their disease-fighting properties. Objective: Understanding the molecular dynamics of oleuropein is crucial to increase olive oil and table olive quality. The objective of this review is to provide the molecular dynamics and computational mapping of oleuropein. Method: The oleuropein molecular bond sequential breaking mechanisms were analyzed through unimolecular reactions under electron spray ionization, collision activated dissociations, and fast atom bombardment mass spectrometry. Results: Oleuropein is a biophenol-secoiridoid expressing different functionalities such as two π-bonds, two esters, two acetals, one catechol, and four hexose hydroxyls within 540 mw. The oleuropein solvent-free reactivity is leading to glucose loss and bioactive aglycone-dialdehydes via secoiridoid ring opening. Conclusion: Oleuropein electron distribution revealed that the free-radical non-polar processes occur from its highest occupied molecular orbital, while the lowest unoccupied molecular orbital is clearly devoted to nucleophilic and base site reactivity. This molecular dynamics and computational mapping of oleuropein could contribute to the engineering of olive-based biomedicine and/or functional food.

Background: Coenzyme Q10 (CoQ10) plays a critical role in mitochondrial oxidative phosphorylation by serving as an electron carrier in the respiratory electron transport chain. CoQ10 also functions as a lipid-soluble antioxidant by protecting lipids, proteins and DNA damaged by oxidative stress. CoQ10 deficiency has been associated with a number of human diseases in which CoQ10 supplementation therapy has been effective in slowing or reversing pathological changes. Oxidative stress is a major contributory factor in the process of retinal degeneration. Method: The related literature was reviewed through searching PubMed using keywords: CoQ10, CoQ10 and oxidative stress, CoQ10 and retinal degeneration. The functions of CoQ10 were summarized and its use in the treatment of age-related macular degeneration and glaucoma highlighted. The therapeutic potential of CoQ10 for other retinal diseases was also discussed. Results: CoQ10 has been applied in different types of neurodegeneration. CoQ10 is detectable in retina and declines with ageing. Early studies showed treatment of CoQ10 improved visual function in patients with age-related macular degeneration. In glaucomatous models, CoQ10 exposure protected ganglion cell death from environmental stress; in glaucoma patients, CoQ10 treatment demonstrated beneficial effects on function of inner retina and enhancement of visual cortical response. Since oxidative stress also plays a critical role in the pathogenesis of diabetic retinopathy and retinitis pigmentosa, CoQ10 is a therapeutic target for both conditions. Conclusion: A wide range of evidence supports a role of CoQ10 in retinal diseases through inhibiting production of reactive oxygen species and protecting neuroretinal cells from oxidative damage.

Background: Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. Objective: In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the β-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases. Results: We describe the binding site in β-adrenergic receptors to understand key factors in ligand recognition along with the proteins activation process. Moreover, we focus on the discovery of new lead compounds that bind the receptors, on the evaluation of virtual screening using the active/ inactive binding site states, and on the structural optimization of known families of binders to improve β-adrenergic affinity. We also discussed strengths and challenges related to the applicability of molecular docking in β-adrenergic receptors. Conclusion: Molecular docking is a valuable technique in computational chemistry to deeply analyze ligand recognition and has led to important breakthroughs in drug discovery and design in the field of β-adrenergic receptors.

Background: Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. Objective: It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain. Methods: Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis. Results: Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome. Conclusions: Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations.

Background: Induced Pluripotent Stem Cell (IPSC) Technology is the most advanced research as it offers an attractive alternative for establishing patient-specific IPSCs to recapitulate phenotypes of not only monogenic diseases (viz. Thalassaemia, Sickle cell anemia, Haemophilia, Tay-Sachs disease), but also late-onset polygenic diseases (viz. Parkinson's disease, Alzheimer's disease, schizophrenia). Over the hindsight, numerous studies of the past and current scientists have led to the production, maturation and understanding of induced pluripotent stem cell technology and its use in basic and clinical research. Methods: A systematic search of peer-reviewed scientific literature and clinical trials in public databases were carried out to summarize the evidence on the use of IPSC. Results: Current review sheds light upon the use of patient-derived iPSC models in drug toxicity, screening and discovery which have been derived after referring to more than 200 articles in literature. Furthermore, their use as disease models was also studied signifying the versatility of iPSC lines. Conclusion: Through this review, we describe the advent of iPSC technology, where we comprehensively cover the generation of iPSCs and their characterization along with their prospective applications using IPSC banks in disease modeling and drug screening.

Background: Gold nanoparticles (AuNPs), owing to their elegant physicochemical properties, have recently been introduced as promising theranostic nanoparticles. Folic acid is a necessary vitamin for cell proliferation. Accordingly, the surface functionalization of AuNP with folic acid may offer a great potential for the development of a strategy to increase the efficiency of cancer diagnosis and therapy based on the new nanotechnology. In this study, we have reviewed the recent progress made in the design and the biomedical application of various folate-conjugated gold nanoparticles (FAuNPs). Methods: We performed a structured search in bibliographic databases and made a comprehensive list of relevant papers. The main subjects considered in this review included (1) methods for the preparation of F-AuNPs, (2) applications of F-AuNPs in computed tomography (CT), and (3) the use of F-AuNPs in targeted cancer therapy. Results: As many as 96 papers were selected for the review. Accordingly, we explained the noncovalent and the covalent methods of fabricating the various types of F-AuNPs. Particular applications of F-AuNP in cancer diagnosis using the CT scan modality were described. In addition, the applications of F-AuNPs in targeted radiation therapy, chemotherapy, and hyperthermia were elucidated in depth. In the hyperthermia section, we presented certain extra explanations on F-AuNP-based laser, radiofrequency, and ultrasoundbased hyperthermia methods. Conclusion: This review identifies the important roles of F-AuNPs in current cancer studies that are being undertaken worldwide. The findings of this review confirm that F-AuNP is a new theranostic agent, which has a great potential for simultaneous cancer therapy and diagnosis.