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5E: New Methods in Drug Development - Biology

5E: New Methods in Drug Development - Biology



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Learning Objectives

  • describe the basis for the following methods used to design drugs:
    1. combinatorial drug development
    2. computer-aided design
    3. in situ click chemistry
  • describe drugs that target specific
    1. proteins
    2. DNA
    3. RNA
  • describe the benefit of drugs that
    1. are mutivalent
    2. perturb equilibrium

The difficulty lies, not in the new ideas, but in escaping the old ones, which ramify, for those brought up as most of us have been, into every corner of our minds. - John Maynard Keynes


Bioinformatics approaches for new drug discovery: a review

Prolonged antibiotic therapy for the bacterial infections has resulted in high levels of antibiotic resistance. Initially, bacteria are susceptible to the antibiotics, but can gradually develop resistance. Treating such drug-resistant bacteria remains difficult or even impossible. Hence, there is a need to develop effective drugs against bacterial pathogens. The drug discovery process is time-consuming, expensive and laborious. The traditionally available drug discovery process initiates with the identification of target as well as the most promising drug molecule, followed by the optimization of this, in-vitro, in-vivo and in pre-clinical studies to decide whether the compound has the potential to be developed as a drug molecule. Drug discovery, drug development and commercialization are complicated processes. To overcome some of these problems, there are many computational tools available for new drug discovery, which could be cost effective and less time-consuming. In-silico approaches can reduce the number of potential compounds from hundreds of thousands to the tens of thousands which could be studied for drug discovery and this results in savings of time, money and human resources. Our review is on the various computational methods employed in new drug discovery processes.

Keywords: Drug discovery Molecular docking Molecular modelling antibiotic resistance bacterial infections.


Cancer Drug Design and Discovery

The ultimate source of information on the design of new anticancer agents, emphasizing small molecules, this newest work covers recent notable successes resulting from the human genome and cancer genomics projects. These advances have provided information on targets involved in specific cancers that are leading to effective medicines for at least some of the common solid tumors. Unique sections explain the basic underlying principles of cancer drug development and provide a practical introduction to modern methods of drug design. Appealing to a broad audience, this is an excellent reference for translational researchers interested in cancer biology and medicine as well as students in pharmacy, pharmacology, or medicinal and biological chemistry and clinicians taking oncology options.

The ultimate source of information on the design of new anticancer agents, emphasizing small molecules, this newest work covers recent notable successes resulting from the human genome and cancer genomics projects. These advances have provided information on targets involved in specific cancers that are leading to effective medicines for at least some of the common solid tumors. Unique sections explain the basic underlying principles of cancer drug development and provide a practical introduction to modern methods of drug design. Appealing to a broad audience, this is an excellent reference for translational researchers interested in cancer biology and medicine as well as students in pharmacy, pharmacology, or medicinal and biological chemistry and clinicians taking oncology options.

Key Features

* Covers both currently available drugs as well as those under development
* Provides a clinical perspective on trials of new anticancer agents
* Presents drug discovery examples through the use of case histories

* Covers both currently available drugs as well as those under development
* Provides a clinical perspective on trials of new anticancer agents
* Presents drug discovery examples through the use of case histories


Abstract

Great success has been witnessed in last decades, some new techniques and strategies have been widely used in drug discovery. In this roadmap, several representative techniques and strategies are highlighted to show recent advances in this filed. (A) A DOX protocol has been developed for accurate protein-ligand binding structure prediction, in which first principle method was used to rank the binding poses. Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%, indicating significant improvement over molecular docking method. (B) Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen, which has been used in hit/lead identification, drug repositioning, and mechanism-of-action studies. Current and emerging methods for virtual target profiling are briefly summarized herein. (C) Research on targeted autophagy to treat diseases has received encouraging progress. However, due to the complexity of autophagy and disease, experimental and in silico methods should be performed synergistically for the entire process. This part focuses on in silico methods in autophagy research to promote their use in medicinal research. (D) Histone deacetylases (HDACs) play important roles in various biological functions through the deacetylation of lysine residues. Recent studies demonstrated that HDACs, which possess low deacetylase activities, exhibited more efficient defatty-acylase activities. Here, we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor. (E) The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area. (F) Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance. (G) Since nitric oxide (NO) exerts anticancer activity depending on its concentration, optimal levels of NO in cancer cells is desirable. In this minireview, we briefly describe recent advances in the research of NO-based anticancer agents by our group and present some opinions on the future development of these agents. (H) The field of photoactivation strategies have been extensively developed for controlling chemical and biological processes with light. This review will summarize and provide insight into recent research advances in the understanding of photoactivatable molecules including photoactivatable caged prodrugs and photoswitchable molecules.


Empowering Students: The 5E Model Explained

Teachers who can incorporate instructional models like the 5E Model into their classrooms help students build a strong foundation of knowledge through active participation.

When choosing an instructional model, teachers seek strategies that help students gain a complete understanding of new concepts. They aim to engage students, motivate them to learn, and guide them toward skill development. One of the ways to do that is by incorporating inquiry-based approaches like the 5E Model, which is grounded in active learning.

Research suggests that there is a set order of events that facilitates learning, known as a learning cycle. Educators J. Myron Atkin and Robert Karplus argued in 1962 that effective learning cycles involve three key elements: exploration, term introduction, and concept application. “In their scheme, exploration allowed the learners to become interested in the subject at hand, raise questions, and identify points of dissatisfaction with their current understanding. Introduction of new ideas and terms, primarily by the instructor, but negotiated by both instructor and students, followed. Finally, concept application provided learners with opportunities within the classroom to apply their new ideas, try out their new understandings in novel contexts, and evaluate the completeness of their understanding,” according to Kimberly D. Tanner in the article “Order Matters: Using the 5E Model to Align Teaching With How People Learn.”


Embryonic development in a dish

Recent studies aimed at producing specific differentiated cells from ESCs or iPSCs have followed the principle established by Wichterle and colleagues [12] and attempted to recapitulate embryonic development in cell culture. At the core of this approach is the recognition that embryonic development occurs as a series of steps, with cells that have multipotential capacity becoming increasingly differentiated (Figure 1). However, even armed with this recognition, success has been somewhat mixed.

The most common approach for regulating cell differentiation is based on coaxing cells through sequential stages of differentiation. The top schematic is generic and could be applied to any cell type. The lower paradigm is one that could be used to produce pancreatic β-cells and is taken from the work of Chen et al. [43]. DE, definitive endoderm EP, endocrine progenitor PP, pancreatic progenitor.

One instructive example is that of Kattman and colleagues [27], who published a very thorough paper describing a protocol to produce cardiac myocytes from ESCs and iPSCs in which they sequentially added morphogenic factors important in the appearance of cardiac muscle. They stressed a few general conclusions: (a) the first step of any differentiation procedure, the induction of the correct germ layer, must occur efficiently (b) quantitative markers of different stages of development are helpful (c) the timing of activation or inhibition of various morphogenic pathways is critical, especially given that the very same pathway can have a stimulatory or an inhibitory influence at different times and (d) the concentration of the inducing factors must be controlled carefully. In essence, this work confirms that the complex environment of the embryo can be reproduced to at least some degree. However, the authors also pointed out that there is significant variation among different cell lines so that protocols may have to be tailored to each, perhaps because individual lines may make variable amounts of their own inducing factors. This would be a significant hurdle if it were necessary to produce cardiac myocytes from tens or hundreds of patient lines for drug toxicity testing. Thus, finding a way of overriding this variability would be a valuable advance.

Again by adopting an analogous strategy, Studer and colleagues [28] have pursued methods for producing particular types of neurons efficiently. Importantly, they introduced a convenient way of regulating early neural induction by treating human ESCs, grown without standard feeder layers, with inhibitors of both TGF-β and bone morphogenetic protein (BMP) signaling [28]. This group went on to show the utility of this technique in the generation of dopaminergic neurons and motor neurons. Subsequent studies confirmed its utility in the derivation of cell types as diverse as neural crest [29] and floor plate [30].


Developing Drugs

Drugs may be accidentally discovered, for example when researching another field. It is well known that Alexander Fleming discoved Penicillin accidentally because of keeping an untidy laboratory while investigating the properties of Staphylococci.

Many people (80% of the World’s population according to WHO) rely on traditional medicines and drugs. This is especially so in less economically developed countries, where there is less knowledge or less money to use use modern drugs.

Some modern drugs are derived from traditionally used ones. For example, Hippocrates used an extract from willow bark to relieve pain, and a similar extract has been used in Britain since the Middle Ages. The active ingredient was later isolated and is now used in Aspirin.

Drugs can be discovered and developed by observing wildlife. Many animals use drugs to protect them from diseases. For example, some birds line their nests with medicinal leaves to protect their young, and some furred animals use citrus oils as insecticides and antiseptics.

A lot of modern drugs have been developed by looking at plants, especially tropical plants because of their great diversity. chemical fingerprinting technology is being used to more effectively screen chemicals for their natural medicinal properties.

Much of recent research has concetrated on looking at Genetics. For example, biologists have been researching how Streptomyces, the main source of new drugs in the past 50 years, codes for the drugs it produces.

Biologists also look at how pathogenic microorganisms interact with human cells. By looking the Cell Receptor Sites used by a specific pathogen, for example by looking at the sequence of amino acids that produces it, drugs can be developed that block that Receptor Site.

Genetics may be of further help in comaring the Human Genome with that of a plant, for example. In doing so, new drug to help humans may be developed.


Analytical chemistry for drug discovery and development

In recent years “pharmaceutical analysis” has benefited strongly from different technological improvements in separation sciences, modern soft impact mass spectrometry methods coupled with liquid chromatography, and the use of bioanalytical tools for molecular recognition such as antibodies and nucleic acid probes. Molecular-biology-based analytical methods for drug analysis facilitated automated high-throughput screening of new drug candidate molecules.

The overall drug development process requires robust, accurate analytical methods able to support all stages of the process: from preclinical studies to drug formulation, purity assessment, and clinical studies.

The strong quality control rules stimulated the development of new concepts in bioanalysis and instruments able to fulfill these requirements.

Pharmaceutical analysis involves a multidisciplinary analytical approach from cell-based assay to sophisticated spectroscopic technologies all of them have to satisfy the need in drug discovery from simple organic molecules to functional proteins used as candidate drugs.

In the present issue a selection of modern analytical approaches for drug discovery and analysis as well as quality control is provided. This special issue is divided into three parts: drug analysis, quality assurance, and drug discovery.

The first section of this issue is focused on the applications in pharmaceutical analysis of the main analytical techniques. Major advantages and critical issues of some promising techniques, including high-performance liquid chromatography, mass spectrometry, capillary electrophoresis, vibrational spectroscopies (infrared and Raman), X-ray diffractometry, and hyperspectral imaging techniques, are highlighted.

Besides, also the estimation of the ability of a drug to bind to plasma proteins is a crucial issue in the early drug discovery stages as well as in clinical practice. The methods of choice to obtain a complete view of these binding mechanisms as well as new approaches are discussed.

Attention is also devoted to the problem of pharmaceutical counterfeiting it has been estimated that 10% of medicines worldwide are likely to be counterfeit and the detection of counterfeit drugs represents a challenge for public health safety. In addition, controlling and assuring the quality of Internet pharmaceuticals has become an important and challenging task for the authorities. This aspect is considered together with available analytical tools to determine the physicochemical properties of the pharmaceutical products purchased through the Internet. In addition, the feasibility of proteomics for quality-control processes in transfusion medicine is also discussed.

A brief overview of the evolution of the current pharmaceutical good manufacturing practices and process analytical technology concepts and a review of their applications in the pharmaceutical industry are provided.

The last section of the issue discusses the main analytical challenges of the drug discovery process, with a special focus on the use of circular dichroism and bioanalytical tools. In particular the application of fluorescence and bioluminescence resonance energy transfer for G-protein-coupled receptors is critically reviewed together with calcium-imaging-based methods.

A major part of this special issue is devoted to cell-based approaches, which are playing an ever-increasing role in drug screening routines. In fact, cell-based assays, thanks to their peculiar advantages of predictivity, possibility of automation, multiplexing, and miniaturization, seem to be appealing tools for the high demands of the early stages of the drug discovery process.

Furthermore, single-cell analysis is becoming a fundamental tool to understand cell-to-cell variability. Innovative microfluidic technologies for single-cell analysis for next-generation pharmacological screening, predictive toxicology, and clinical oncology are also discussed and an analytical perspective about the impact of microfluidics on the detection and characterization of biomacromolecules involved in pathological processes is provided.

Aldo Roda is Full Professor of Analytical Chemistry at the Alma Mater Studiorum, University of Bologna. His research activities encompass topics related to bioanalytical chemistry and biochemiluminescence, biosensors, drug analysis, and bioanalytical mass spectrometry for proteomics.

He has authored more than 400 papers and book chapters published in international journals in the fields of analytical chemistry, biochemistry, physiology, medicinal chemistry, and clinical chemistry and more than 25 international patents on new bile acids and antioxidant drugs, new analytical devices and biosensors, and new luciferases.

He is Editor of Analytical and Bioanalytical Chemistry and Luminescence: The Journal of Biological and Chemical Luminescence. He is Councilor on the Advisory Board of the International Society for Bioluminescence and Chemiluminescence (ISBC), a member of Accademia delle Scienze dell’Istituto di Bologna, and a member of the councilor board of the Istituto Nazionale di Biostrutture e Biosistemi (INBB) for biotechnology.