Journal ArticleDOI
Synopsis of some recent tactical application of bioisosteres in drug design.
TLDR
In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates.Abstract:
The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.read more
Citations
More filters
Journal ArticleDOI
Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
TL;DR: In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
Journal ArticleDOI
Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond.
Journal ArticleDOI
Practical and innate carbon–hydrogen functionalization of heterocycles
Yuta Fujiwara,Janice A. Dixon,Fionn O’Hara,Erik Daa Funder,Darryl D. Dixon,Rodrigo A. Rodriguez,Ryan D. Baxter,Bart Herlé,Neal W. Sach,Neal W. Sach,Michael R. Collins,Michael R. Collins,Yoshihiro Ishihara,Phil S. Baran +13 more
TL;DR: It is reported that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild, operationally simple formation of medicinally relevant C–C bonds while reacting in a complementary fashion to other innate C–H functionalization methods.
Journal ArticleDOI
Organosilicon Molecules with Medicinal Applications
TL;DR: Applications such as inhibitor design, imaging, drug release technology, and mapping inhibitor binding are discussed.
Journal ArticleDOI
Radicals: Reactive Intermediates with Translational Potential
TL;DR: This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history, and studies from the laboratory are discussed along with recent developments emanating from others in this burgeoning area.
References
More filters
Journal ArticleDOI
Fluorine in Pharmaceuticals: Looking Beyond Intuition.
TL;DR: Experimental progress in exploration of the specific influence of carbon-fluorine single bonds on docking interactions is reviewed and complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank is added.
Journal ArticleDOI
Fluorine in medicinal chemistry.
TL;DR: This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
MonographDOI
The weak hydrogen bond : in structural chemistry and biology
TL;DR: In this paper, the weak hydrogen bond in supramolecular chemistry and biological structures is discussed. But weak and non-conventional hydrogen bonds are not considered in this paper.
Journal ArticleDOI
Understanding organofluorine chemistry. An introduction to the C–F bond
TL;DR: Fundamental aspects of the C-F bond are explored to rationalise the geometry, conformation and reactivity of individual organofluorine compounds.