Current Medicinal Chemistry - Volume 27, Issue 35, 2020

Therapeutic activity of a significant majority of drugs is determined by their interactions with proteins. Databases of drug-protein interactions (DPIs) primarily focus on the therapeutic protein targets while the knowledge of the off-targets is fragmented and partial. One way to bridge this knowledge gap is to employ computational methods to predict protein targets for a given drug molecule, or interacting drugs for given protein targets. We survey a comprehensive set of 35 methods that were published in high-impact venues and that predict DPIs based on similarity between drugs and similarity between protein targets. We analyze the internal databases of known PDIs that these methods utilize to compute similarities, and investigate how they are linked to the 12 publicly available source databases. We discuss contents, impact and relationships between these internal and source databases, and well as the timeline of their releases and publications. The 35 predictors exploit and often combine three types of similarities that consider drug structures, drug profiles, and target sequences. We review the predictive architectures of these methods, their impact, and we explain how their internal DPIs databases are linked to the source databases. We also include a detailed timeline of the development of these predictors and discuss the underlying limitations of the current resources and predictive tools. Finally, we provide several recommendations concerning the future development of the related databases and methods.

Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary metabolites in one or more parts of the plant. The diverse secondary metabolites play an important role in the prevention and cure of various diseases including neurodegenerative diseases like Alzheimer’s disease. Naturally occurring compounds such as flavonoids, polyphenols, alkaloids, and glycosides found in various parts of the plant and/or marine sources may potentially protect neurodegeneration as well as improve memory and cognitive function. Many natural compounds show anti-Alzheimer activity through specific pharmacological mechanisms like targeting β-amyloid, Beta-secretase 1 and Acetylcholinesterase. In this review, we have compiled more than 130 natural products with a broad diversity in the class of compounds, which were isolated from different sources showing anti- Alzheimer properties.

The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.

Background: Developing a controllable drug delivery system is imperative and important to reduce side effects and enhance the therapeutic efficacy of drugs. Metal-organic frameworks (MOFs) an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers have attracted increasing attention in the recent years owing to the unique physical structures possessed, and the potential for vast applications. The superior properties of MOFs, such as well-defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, have made them promising candidates as drug delivery hosts. MOFs for drug delivery is of great interest and many very promising results have been found, indicating that these porous solids exhibit several advantages over existing systems. Objective: This review highlights the latest advances in the synthesis, functionalization, and applications of MOFs in drug delivery, and has classified them using drug loading strategies. Finally, challenges and future perspectives in this research area are also outlined.

This review presents the detailed account of factors leading to cancer and design strategy for the synthesis of benzimidazole derivatives as anticancer agents. The recent survey for cancer treatment in Cancer facts and figures 2017 American Chemical Society has shown progressive development in fighting cancer. Researchers all over the world in both developed and developing countries are in a continuous effort to tackle this serious concern. Benzimidazole and its derivatives showed a broad range of biological activities due to their resemblance with naturally occurring nitrogenous base i.e. purine. The review discussed benzimidazole derivatives showing anticancer properties through a different mechanism viz. intercalation, alkylating agents, topoisomerases, DHFR enzymes, and tubulin inhibitors. Benzimidazole derivatives act through a different mechanism and the substituents reported from the earlier and recent research articles are prerequisites for the synthesis of targeted based benzimidazole derivatives as anticancer agents. The review focuses on an easy comparison of the substituent essential for potency and selectivity through SAR presented in figures. This will further provide a better outlook or fulfills the challenges faced in the development of novel benzimidazole derivatives as anticancer.

Nanotechnology offers promising tools in interdisciplinary research areas and getting an upsurge of interest in cancer therapeutics. Organic nanomaterials and inorganic nanomaterials bring revolutionary advancement in cancer eradication process. Oncology is achieving new heights under nano technological platform by expediting chemotherapy, radiotherapy, photo thermodynamic therapy, bio imaging and gene therapy. Various nanovectors have been developed for targeted therapy which acts as “Nano-bullets” for tumor cells selectively. Recently combinational therapies are catching more attention due to their enhanced effect leading towards the use of combined organicinorganic nano platforms. The current review covers organic, inorganic and their hybrid nanomaterials for various therapeutic action. The technological aspect of this review emphasizes on the use of inorganic-organic hybrids and combinational therapies for better results and also explores the future opportunities in this field.

Background: Thromboangiitis obliterans (TAO) is a nonatherosclerotic thromboticocclusive vasculitis that affects the vessels of the small and medium-sized extremities. No explicit etiology or pathogenesis of TAO has been proven, and more effective treatments are needed. Objective: The study aimed to summarize and present an overview of recent advances regarding the risk factors, mechanisms and treatments of TAO and to organize the related information in figures to provide a comparatively complete reference. Methods: We searched PubMed for English-language literature about TAO without article type limits, including articles about the risk factors, pathological mechanisms and treatments of TAO in the last 10 years with essential supplements (references over ranges and English abstracts of Russian literature). Results: After screening content of works of literature, 99 references were evaluated. We found that risk factors of TAO include smoking, gene factors and periodontal diseases. The underlying mechanism of TAO involves oxidative stress, immunity, hemodynamic changes, inflammation and so on. Moreover, similarities in genetic factors and cigarette relevance existed between periodontal diseases and TAO, so further study of relationship was required. For TAO treatment, medicine, endovascular intervention and revascularization surgery, autologous cell therapy and novel therapies were also mentioned. Besides, a hypothesis that infection triggers autoimmunity in TAO could be speculated, in which TLR4 plays a key role. Conclusion: 1. A hypothesis is put forward that infections can trigger autoimmunity in TAO development, in which TLR4, as a key agent, can activate immune signaling pathways and induce autoimmune cytokines expression. 2. It is suggested to reconsider the association between periodontal diseases and TAO, as they share the same high-risk population. Controlling periodontal disease severity in TAO studies may provide new clues. 3. For TAO treatment, endovascular intervention and autologous cell therapy both showed promising long-term therapeutic effectiveness, in which autologous cell therapy is becoming more popular, although more clinical comparisons are needed.

Autoimmune hepatitis is a necroinflammatory process of liver, featuring interface hepatitis by T cells, macrophages and plasma cells that invade to periportal parenchyma. In this process, a variety of cytokines are secreted and liver tissues undergo fibrogenesis, resulting in the apoptosis of hepatocytes. Autophagy is a complementary mechanism for restraining intracellular pathogens to which the innate immune system does not provide efficient endocytosis. Hepatocytes with their particular regenerative features are normally in a quiescent state, and, autophagy controls the accumulation of excess products, therefore the liver serves as a basic model for the study of autophagy. Impairment of autophagy in the liver causes the accumulation of damaged organelles, misfolded proteins and exceeded lipids in hepatocytes as seen in metabolic diseases. In this review, we introduce autoimmune hepatitis in association with autophagy signaling. We also discuss some genes and proteins of autophagy, their regulatory roles in the activation of hepatic stellate cells and the importance of lipophagy and tyrosine kinase in hepatic fibrogenesis. In order to provide a comprehensive overview of the regulatory role of autophagy in autoimmune hepatitis, the pathway analysis of autophagy in autoimmune hepatitis is also included in this article.