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The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Combinatorial chemistry involves the use of the basic building blocks in biochemistry, either the 20 amino acids or 4 nucleic acids, to build new molecules. All the different combinations of a number of building blocks can be created, for example, the use of 10 different amino acids can result in over 3.5 million decapeptide compounds. Huge libraries of compounds are produced, which require screening through HTS and the use of informatics to help sort out the structures and, especially, the activities of all such new compounds.
Evaluation Models for Drug Transport Across the Blood–Brain Barrier
Published in Sahab Uddin, Rashid Mamunur, 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.
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Concerning future prospects of enzyme inhibitors as drugs, there is a never-ending need to develop safe, efficient, and affordable new treatment strategies as alternatives to existing ones. These efforts will be supported by using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition (Brian et al., 2016). Another important aspect is the further improvement of existing structure-based or ligand-based methods and tools of computer-aided drug design and discovery which increases the hit rate of novel drug compounds due to using a much more targeted search than traditional HTS and combinatorial chemistry (Sliwoski et al., 2014). Furthermore, one of the core areas in drug development should be the neglected diseases The Drugs for Neglected Diseases initiative (DNDi) is a drug research and development (R&D) organization that is developing new treatments for neglected patients.
Contemporary medicinal-chemistry strategies for discovery of blood coagulation factor Xa inhibitors
Published in Expert Opinion on Drug Discovery, 2019
Xia Hao, Xiaofang Zuo, Dongwei Kang, Jian Zhang, Yuning Song, Xinyong Liu, Peng Zhan
The existence of ubiquitous motifs in FXa inhibitors is reminiscent of the concept of privileged structures in medicinal chemistry. By applying a fragment-based drug discovery strategy, the ubiquitous motifs derived from databases of known FXa inhibitors with high potency, high oral bioavailability, and favorable PK can be used as basic pharmacophoric elements for the generation of compound libraries that should be capable of yielding high-quality hits. Other new medicinal-chemistry approaches (such as crystallographic overlay-based pharmacophore hybridization and fragment deconstruction) and dynamic combinatorial chemistry have already assisted the discovery of new drug-candidate prototypes. Increased crystallography throughput and increasingly sophisticated molecular modeling techniques have been critical to our understanding of how lead compounds bind to FXa and related serine proteases; they have also become essential to the process of evolving these compounds into highly optimized and orally bioavailable FXa inhibitors with decreased bleeding risk.
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.
Recent applications of click chemistry in drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Xiangyi Jiang, Xia Hao, Lanlan Jing, Gaochan Wu, Dongwei Kang, Xinyong Liu, Peng Zhan
One of the most formidable challenges in medicinal chemistry is rationalizing and accelerating lead discovery and optimization. A versatile chemical toolbox is essential for this purpose. In this context, CuAAC click chemistry provides a simple and selective synthetic tool for the preparation of triazole motifs, which are frequently found in drugs and bioactive molecules. Based on the isosteric replacement principle, triazole heterocycles can replace amide bonds, various heteroaromatic groups and other functional groups in lead compounds while retaining key hydrogen bonds and hydrophobic interactions, thereby expanding the structural diversity of compound libraries, and offering the potential to improve the potency, physicochemical and pharmacokinetic properties of lead compounds. In addition, click chemistry is widely used in the synthesis of (conformationally restricted) peptidomimetics or chemical probes. The triazole ring can be used to connect key pharmacophore elements with peripheral substituents to construct privileged structure-derived compound libraries. In short, the combination of click chemistry with high-throughput screening or molecular self-assembly systems (dynamic combinatorial chemistry) provides a rapid, efficient and reliable tool for the discovery of bioactive molecules. Consequently, CuAAC click chemistry-inspired drug discovery remains a hot research topic in the field of medicinal chemistry [33].