Evaluation Models for Drug Transport Across the Blood–Brain Barrier
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
It has been seen that physiological responses are difficult to obtain in vivo (Xu et al., 2016). To overcome this issue, a good number of in vitro models are developed which helps to figure out the functioning associated with various pathological conditions (He et al., 2014). The barrier acts as an interface performing various specialized functions like protection from injuries as well as for the passage of molecules. The in vitro BBB simulation is a major hurdle in mimicking the physiological characteristics, which have to correlate with the in vivo condition. A high throughput screening can be achieved with the help of combinatorial chemistry. The structure of the barrier and its changes associated with various pathological conditions can be studied. In this chapter authors presented, the different types of in vitro and in vivo models. In addition, the various criteria in the selection of an ideal model are discussed.
Small Animal Imaging and Therapy
George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos in Handbook of Small Animal Imaging, 2018
The paradigm shift toward combinatorial chemistry and the availability of high throughput screening approaches resulted in target-based drug and imaging probe development that affect a single target. This implies that a disease and its progression is dependent on a single protein expression product, which is in clear contrast to the approaches using physiology as an end point that can be affected by multiple targets. For new drug or imaging agent development, this could represent an oversimplification leading to a genetic reductionism and inability to develop optimal animal models to simulate a clinical situation. For example, this oversimplification can reduce a disease to a single genetic abnormality modeled with transgenic animals but it may not represent a clinical multifactorial disease. As a result, fully appropriate animal models for many human diseases are not yet available which makes a translation of target efficacy to disease efficacy less certain. Recent recommendation for development of drug and molecular imaging agents is to combine a rational target-based approach with strong physiology and disease focus (Sams-Dodd 2005).
Drug Design, Synthesis, and Development
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Rational design of drugs to an identified target, can often take the approach of combinatorial chemistry, known as the molecular fragments technique, where sections of a compound that are discovered to bind well to a section of the target are spatially positioned and a scaffold section of the molecule is designed to hold the fragments in these positions. This is how Glaxo Smith Kline and Roche came to develop similar structures independently. The next stage is lead optimisation, where drug properties are optimised. For example, the improved oral bioavailability of Tamiflu compared to Relenza. Idealised drug criteria for an effective medicine involve: high affinity for the target, safe/well tolerated by the patient, synergistic with other drugs when used in combination therapy, and can be taken orally with minimal dosing frequency. The closer a drug adheres to these requirements, the greater its potential as a medicine.
Approaching Target Selectivity by De Novo Drug Design
Published in Expert Opinion on Drug Discovery, 2019
Thomas Fischer, Silvia Gazzola, Rainer Riedl
The chemical space opens up enormous possibilities to the creativity of medicinal chemists for the design of next-generation drug molecules for targeted therapy. This is both a blessing and a curse because in addition to the potential large number of effective new structural elements, it is even more likely that inactive molecules are generated. Therefore, in order to increase the likelihood of technical success in drug discovery toward potent and selective modulators of therapeutically relevant biological targets, different techniques have emerged over time. All of these techniques, such as combinatorial chemistry, high throughput screening, and automated synthesis, have left their mark on the discovery of drugs. In this context, de novo drug design plays a special role, because it embodies the dream of every medicinal chemist: to create a new drug cost-effectively, precisely and with the desired properties in terms of effectiveness and selectivity from scratch.
HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
Published in Pharmaceutical Biology, 2019
Matthias Hamburger
The relevance of natural products for drug discovery and development is undisputed. In the nineteenth and early twentieth century, drug substances were mainly natural products, but during the twentieth century derivatives of natural products and natural product-inspired fully synthetic drug substances became increasingly important. But even in recent years approximately 35% of the new chemical entities approved as drugs were directly derived from natural products (Newman and Cragg 2012). Despite this impressive track record, a steady decline of interest for natural products has occurred within the pharmaceutical industry. Several factors have led to this apparently paradoxical situation, for example, the advent of new technologies such as combinatorial chemistry which appeared at one time more promising and ‘easier’ for generating screening libraries. Also, with the triumph of high throughput screening (HTS) in the 1990s, natural product research struggled to find its place in the rapidly evolving drug discovery landscape. It became increasingly clear that the classical approach of preparative bioactivity-guided fractionation was incompatible with the fast turnaround and tight deadlines of modern screening programs (Potterat and Hamburger 2013).
An outlook on using serial femtosecond crystallography in drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Alexey Mishin, Anastasiia Gusach, Aleksandra Luginina, Egor Marin, Valentin Borshchevskiy, Vadim Cherezov
Modern drug discovery is a complex process that, in general, consists of several major steps, including initial target selection and validation, hit identification, hit-to-lead optimization, candidate selection, animal and clinical trials (Figure 1). Traditionally, initial hit identification relies on high-throughput screening (HTS), which is typically limited to assaying libraries of less than a few million compounds out of possible virtual chemical space consisting of over 1063 drug-like small molecules [8]. Combinatorial chemistry along with fragment-based screening bring promise to increase potential coverage of the chemical space, however, these approaches come with additional challenges related to low binding affinity for fragments and to the need for more extensive optimization of fragment-based hits [9]. After initial hits are identified, their optimization is performed iteratively via multiple rounds of structure–activity relationship (SAR) studies [10]. Overall, it takes from several months to a few years to select the most promising candidate for clinical trials.
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