Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.

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Flavonoids: an overview

Drug discovery utilizes chemical biology and computational drug design approaches for the efficient identification and optimization of lead compounds. Chemical biology is mostly involved in the elucidation of the biological function of a target and the mechanism of action of a chemical modulator. On the other hand, computer-aided drug design makes use of the structural knowledge of either the target (structure-based) or known ligands with bioactivity (ligand-based) to facilitate the determination of promising candidate drugs. Various virtual screening techniques are now being used by both pharmaceutical companies and academic research groups to reduce the cost and time required for the discovery of a potent drug. Despite the rapid advances in these methods, continuous improvements are critical for future drug discovery tools. Advantages presented by structure-based and ligand-based drug design suggest that their complementary use, as well as their integration with experimental routines, has a powerful impact on rational drug design. In this article, we give an overview of the current computational drug design and their application in integrated rational drug development to aid in the progress of drug discovery research.

https://link.springer.com/content/pdf/10.1007%2Fs12272-015-0640-5.pdf

Role of computer-aided drug design in modern drug discovery

It is widely accepted that modern QSAR began in the early 1960s. However, as long ago as 1816 scientists were making predictions about physical and chemical properties. The first investigations into the correlation of biological activities with physicochemical properties such as molecular weight and aqueous solubility began in 1841, almost 60 years before the important work of Overton and Meyer linking aquatic toxicity to lipid-water partitioning. Throughout the 20th century QSAR progressed, though there were many lean years. In 1962 came the seminal work of Corwin Hansch and co-workers, which stimulated a huge interest in the prediction of biological activities. Initially that interest lay largely within medicinal chemistry and drug design, but in the 1970s and 1980s, with increasing ecotoxicological concerns, QSAR modelling of environmental toxicities began to grow, especially once regulatory authorities became involved. Since then QSAR has continued to expand, with over 1400 publications annually from 2011 onwards. KeywoRDS 1816, Corwin Hansch, Crum Brown and Fraser, Descriptors, Environmental Sciences, Newer Approaches, Pharmacology, Statistics INTRoDUCTIoN: wHAT IS A QSAR? Humans are inherently inquisitive. Even small children persistently ask “Why?”. So it is no surprise that for many years scientists have asked why some substances have a beneficial effect on the body, whilst others are toxic, and why some are more beneficial, or more toxic, than are others. That led Crum Brown and Fraser (1868-1869) to postulate that “there can be no reasonable doubt but that a relation exists between the physiologic action of a substance (Φ) and its chemical composition and constitution (C)”. Hence Φ = fC. They did not go on to suggest what functions of composition and constitution might be important. Nevertheless, their equation is a valid generic quantitative structure-activity relationship (QSAR). They also pointed out that “to discover f we produce a known change on the constitution by which it becomes C + ΔC, and examine the corresponding change of physiological action which has become Φ + ΔΦ. We thus obtain the relation between ΔC and ΔΦ, and by sufficiently varying C and ΔC, we may hope to get at all events an approximate solution of the problem”. That was a remarkably prescient statement, for it is exactly how QSAR modelling is performed (Kubinyi, 1993). Hence, in Crum Brown and Fraser’s terminology, a QSAR equation would be: Φ = c1C1 + c2C2 + c3C3 +...cnCn (1)

The History and Development of Quantitative Structure-Activity Relationships (QSARs)

This paper is an overview of the most significant and impactful interpretation approaches of quantitative structure–activity relationship (QSAR) models, their development, and application. The evolution of the interpretation paradigm from “model → descriptors → (structure)” to “model → structure” is indicated. The latter makes all models interpretable regardless of machine learning methods or descriptors used for modeling. This opens wide prospects for application of corresponding interpretation approaches to retrieve structure–property relationships captured by any models. Issues of separate approaches are discussed as well as general issues and prospects of QSAR model interpretation.

Interpretation of Quantitative Structure-Activity Relationship Models: Past, Present, and Future.

The modified thermal treatment method via alternate oxygen and nitrogen flow was successfully employed to synthesize very narrow and pure Ag nanoparticles. The structural and optical properties of the obtained metal nanoparticles at different calcination temperatures between 400 and 800 °C were studied using various techniques. The FTIR and EDX confirmed the formation of Ag nanoparticles without a trace of impurities. The XRD spectra revealed that the amorphous sample at 30 °C had transformed into the cubic crystalline nanostructures at the calcination temperature of 400 °C and higher. The TEM images showed the formation of spherical Ag nanoparticles in which the average particle size decreased with increasing calcination temperature from 7.88 nm at 400 °C to 3.29 nm at 800 °C. The optical properties were determined by UV-vis absorption spectrophotometer, which showed an increase in the conduction band of Ag nanoparticles with increasing calcination temperature from 2.75 eV at 400 °C to 3.04 eV at 800 °C. This was due to less attraction between conduction electrons and metal ions as the particle size decreases in corresponding to fewer numbers of atoms that made up the metal nanoparticles.

Structural and Optical Properties of Ag Nanoparticles Synthesized by Thermal Treatment Method.

The quantitative structure activity relationship (QSAR) study is the most cited and reliable computational technique used for decades to obtain information about a substituent's physicochemical property and biological activity. There is step-by-step development in the concept of QSAR from 0D to 2D. These models suffer various limitations that led to the development of 3D-QSAR. There are large numbers of literatures available on the utility of 3D-QSAR for drug design. Three-dimensional properties of molecules with non-covalent interactions are served as important tool in the selection of bioactive confirmation of compounds. With this view, 3D-QSAR has been explored with different advancements like COMFA, COMSA, COMMA, etc. Some reports are also available highlighting the limitations of 3D-QSAR. In a way, to overcome the limitations of 3D-QSAR, more advanced QSAR approaches like 4D, 5D and 6D-QSAR have been evolved. Here, in this present review we have focused more on the present and future of more predictive models of QSAR studies. The review highlights the basics of 3D to 6D-QSAR and mainly emphasizes the advantages of one dimension over the other. It covers almost all recent reports of all these multidimensional QSAR approaches which are new paradigms in drug discovery.

Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review

The microbiome actually deals with micro-organisms that are associated with indigenous body parts and the entire gut system in all animals, including human beings. These microbes are linked with roles involving hereditary traits, defence against diseases and strengthening overall immunity, which determines the health status of an organism. Considerable efforts have been made to find out the microbiome diversity and their taxonomic identification in finfish and shellfish and its importance has been correlated with various physiological functions and activities. In recent past due to the availability of advanced molecular tools, some efforts have also been made on DNA sequencing of these microbes to understand the environmental impact and other stress factors on their genomic structural profile. There are reports on the use of next-generation sequencing (NGS) technology, including amplicon and shot-gun approaches, and associated bioinformatics tools to count and classify commensal microbiome at the species level. The microbiome present in the whole body, particularly in the gut systems of finfish and shellfish, not only contributes to digestion but also has an impact on nutrition, growth, reproduction, immune system and vulnerability of the host fish to diseases. Therefore, the study of such microbial communities is highly relevant for the development of new and innovative bio-products which will be a vital source to build bio and pharmaceutical industries, including aquaculture. In recent years, attempts have been made to discover the chemical ingredients present in these microbes in the form of biomolecules/bioactive compounds with their functions and usefulness for various health benefits, particularly for the treatment of different types of disorders in animals. Therefore, it has been speculated that microbiomes hold great promise not only as a cure for ailments but also as a preventive measure for the number of infectious diseases. This kind of exploration of new breeds of microbes with their miraculous ingredients will definitely help to accelerate the development of the drugs, pharmaceutical and other biological related industries. Probiotic research and bioinformatics skills will further escalate these opportunities in the sector. In the present review, efforts have been made to collect comprehensive information on the finfish and shellfish microbiome, their diversity and functional properties, relationship with diseases, health status, data on species-specific metagenomics, probiotic research and bioinformatics skills. Further, emphasis has also been made to carry out microbiome research on priority basis not only to keep healthy environment of the fish farming sector but also for the sustainable growth of biological related industries, including aquaculture.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpn.13619

Aquaculture industry prospective from gut microbiome of fish and shellfish: An overview.

Number of attempts has been made to cryopreserve fish and shellfish gametes and success has been achieved to establish only sperm banks in case of some commercially important fish. In shellfish also particularly in shrimps though the sperm cryopreservation was successful, no attempts were made to develop sperm banks. As far as cryobanking of egg and embryos of fish and shellfish is concerned, less research efforts were made that too with limited success. Number of reasons has been given for the failure of egg /embryo cryopreservation and the main barriers speculated are low membrane permeability in the eggs, and the large yolk mass of the oocyte and the presence of compartments in early developing embryos. Both these factors result in ice crystal formation during the freezing process. In addition, the oocytes and embryos are prone to chilling injuries unrelated to ice crystal damage. There are number of other problems reported by several workers in the egg/embryo cryobanking protocols which are elaborately discussed in the present paper. There is an urgent need to develop a viable cryobanking technology for fish egg/embryos to enhance fish production in captive condition. Attempt to cryopreserve larvae of aquatic animals is another challenge coming up in recent past. The purpose of the present review is to collect comprehensive information on the efforts so far made on fish and shellfish egg and embryo cryobanking, assess the challenges in the development of viable technology and plan for future research for making this technology viable and cost effective.

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Cryobanking of Fish and Shellfish Egg, Embryos and Larvae: An Overview

In this article we have studied the antimicrobial activity of silver nanoparticles with five different types of bacteria. Silver nanoparticles were chemically synthesized using silver nitrate as a precursor material and tri sodium citrate as reducing agent. UV-Vis spectroscopy and Scanning Tunnelling Microscopy (STM) were used to study the absorption spectra and surface morphology of Silver nanoparticles. The antimicrobial activity of silver nanoparticles was investigated against five different types of microorganisms such as Bacillus subtilis, Bacillus megaterium, Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus.

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Synthesis Of Silver Nanoparticles By Chemical Reduction And Their Antimicrobial Activity

In recent past several efforts have been made to analyze the symptoms, causes, and cure of Alzheimer’s disease (AD) and also to reveal biochemical changes and pathogenesis of the brain affected with AD. Several studies indicated the main cause of the disease is deposition of necrotic β-amyloid plaques in the brain. The enzymes β-secretase and γ-secretase catalyze the β-amyloid production. It has also been observed that the cells producing acetylcholine, a major neurotransmitter, are destroyed by two closely related enzymes namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in AD progression leading to cognitive disabilities. Hence, the research is going on in finding the inhibitors for these enzymes which will help to either prolong or cure the AD. Discovering the inhibitors for AChE and BChE without side effects remains a major challenge as the AChE and BChE inhibiting drugs available possess several side effects. Several new drugs are being discovered utilizing medicinal plant resources. Uses of flavonoids as plant secondary metabolites are being tried for the treatment of AD. Efforts are being made to apply computational knowledge to streamline the drug discovery process. Nevertheless, blood-brain barrier (BBB) permeation plays a vital role in drug discovery. BBB a physical barrier in the brain through which the central nervous system therapeutic molecule has to permeate for its activity. Finding the potent lead candidates capable of crossing the BBB remains to be a major challenge in neurodegenerative diseases. In the present review, attempts have been made to discuss on all these important aspects. Keywords: Alzheimer’s disease, Amyloid precursor protein, β-amyloid, Blood-brain barrier, Flavonoids, Molecular docking, Multi-enzyme targeting.

Sanjay N. Harke

Papers

Recent Advances in Multidimensional QSAR (4D-6D): A Critical Review

Aquaculture industry prospective from gut microbiome of fish and shellfish: An overview.

Cryobanking of Fish and Shellfish Egg, Embryos and Larvae: An Overview

Synthesis Of Silver Nanoparticles By Chemical Reduction And Their Antimicrobial Activity

Alzheimer’s and current therapeutics: a review