Frontiers in Drug Design and Discovery

The needs for purified proteins in modern medicine, research and industrial application are immense and production of proteins using recombinant technology offers solutions; proteins are used in simple laboratory experiments like protein-protein and protein-DNA interactions and in diagnostic, therapeutic and industrial applications. Some examples of the application of purified recombinant proteins for the treatment of diseases include clotting factors (Factor VIII and IX) for the treatment of hemophilia, insulin-dependent diabetes, and adenosine deaminase for severely compromised immune disease. Recently, human monoclonal antibodies, like anti-tumor necrosis factor-α (Adalimumab) for the treatment of rheumatoid arthritis and Repatha (proprotein convertase subtilisin kexin type 9 or PCSK9) inhibitor antibody for the treatment of and reduction in the risk of myocardial infarction, stroke and revascularization of coronary artery diseases, are produced using protein overexpression methodology described in this chapter. Use of recombinant protein technologies has enabled industries to produce proteins of human significance at a tremendous pace. Production of therapeutic proteins at large scale for millions of individuals to treat diseases is one of the essential needs of mankind. From simple proteins like albumin, growth factors, cytokines, viral vaccines and human monoclonal antibodies, all are being produced utilizing the recombinant protein expression technology and purification processes, whether in a laboratory or biopharming scale in microorganisms, animals and/or plants. This chapter summarizes various recombinant expression systems and their pharmaceutical applications.

Both virus like particles (VLPs) and virus nanoparticles (VNPs) are viable platforms for the transportation of drugs, imaging agents, immunogenic ligands and other materials. They can be loaded with genetic material and/or drugs for therapeutic purposes. VLPs possess multivalent molecular settings, which help stimulate various molecular interactions for a potent immune response. VNPs are biodegradable and biocompatible nanoparticles that occur in nature and can be modified with genetic and chemical protocols for therapeutic purposes. There has been considerable research on the use of different VLPs and VNPs as safe and viable platforms for vaccine development, tumor therapy and other medical applications. The following chapter provides insight into applications of plant VLPs and VNPs in medicine.

Emergence of treatment-resistant depression is the new challenge before us. As antidepressants currently existing in the market are of little or no use, clinicians are looking for newer and effective antidepressants to handle situations. Inhibition of Monoamine oxidase, an effective strategy discontinued a few decades before due to selectivity related issues. Technological advancement in chemistry and biology interface is now availing hopes of achieving the design and synthesis of novel, isoform-selective and tissue-specific inhibitors. This has renewed the interest in reexploring the MAO inhibitors in the past decade. Under this background, the chapter reviews MAO inhibitory activity and antidepressant activity of 4, 5-dihydro-1Hpyrazole derivatives reported to date. Since different sources of enzymes (rat, bovine, human, etc.) were used by different groups to evaluate the newly synthesized compounds, any discussion on structure-activity-relationship may not be justified. Hence, the authors made an attempt to summarize the literature based on the chemical architecture of the compounds that may help the medicinal chemists to further explore the unexplored chemical space. Further, efforts by the scientific community to report the effect of chirality of compounds on activity and selectivity, experimentally or through computational simulations are also documented.

Alcohol dependence is one of the top priority public health problems on a global scale. The costs of medical treatments of patients with alcohol dependence, a decrease in labor productivity, an increased risk of developing somatic and mental disorders, and early mortality are all consequences of acute and chronic alcohol abuse. The brain is one of the main targets of alcohol intoxication. Extensive neurobiological studies have revealed a number of synaptic and extra-synaptic mechanisms, affected by alcohol. A primary target of it is GABAergic transmission. Nevertheless, the exciting and disinhibiting actions of alcohol at the system and cellular levels have not been satisfactorily elucidated. It remains unclear whether effects of ethanol are highly complex, manifested only at the level of entire brain or concerns also individual cells, their subcellular structures, organelles, ion channels and receptors. With this approach, small, cultured neural networks that are isolated from the rest of the brain are of particular interest. A serious problem of modern pharmaceuticals is the lack of drugs that have a therapeutic effect on alcohol toxicity of the brain and nervous system, despite the abundance of so-called “traditional medicines”. Substances obtained from some herbs containing a mixture of biologically active substances that exhibit a wide range of properties are of particular interest. Among them - flavonoids, which are polyphenols of plant origin and often reveal a sign of sedative, neuroprotective, antidepressant properties, and may improve cognitive function. The aims of our study is to reveal the mechanisms of various concentrations of ethanol, as well as its chronic effects on the functional properties of neurons in small neural networks such as the primary neuronal culture of the rat hippocampus. We have also performed a complex neuropharmacology screening and the study of flavonoids, extracted from Scrophulariaceae plant family, which is known in the traditional medicine for its antialcohol properties.

The recent advances in materials science have enabled great achievements in the development of polymer scaffolds, which can constitute innovative platforms for the development of novel topical drug delivery systems (TDDS) associated with sitespecific or prolonged drug release. The application of polymer scaffolds as drug delivery systems often relies on their combination with many types of nanocarriers, such as liposomes, solid nanoparticles, micelles, nanogels and metallic nanoparticles. The combination of polymer scaffolds and drug nanocarriers and the association of controlled drug release properties provide novel materials, considered hybrid as they gather two therapeutic effects: scaffolding and drug delivery. Such hybrid scaffolds have been shown to be suitable for delivering drugs at controlled rates and site distribution. Many drug carriers are often associated with stability issues, drug leaking or considerable interaction with undesirable cells, hindering their clinical function. Hence, for topical application, drug nanocarriers are often introduced in conventional secondary vehicles such as creams and lotions in order to provide the viscosity, extended residence time and adhesiveness, properties necessary for the administration route. In addition, smart stimuli-responsive polymers can be used in the formulation of both scaffolds and nanocarriers, being promising approaches in the topical treatment of various diseases. In this context, hybrid smart polymer-based scaffolds are versatile platforms for the development of novel TDDS. Such smart materials, in addition to being able to combine the benefits of different structural components, can also respond to external stimuli such as temperature, pH, and redox status, which can increase the effectiveness of therapeutic agents and decrease harmful effects on the surrounding tissue. In this chapter, the different polymer-based scaffolds, most nanocarriers and stimuli-responsive polymers are described as well as their most varied applications in the field of technological development of topical delivery systems for ideal drugs, which is still a challenge for formulation scientists.