Chapter 7 chemical bonding and molecular geometry figure 7. Scientists have now developed a new tool to use halogen bonds for drug discovery. This study would help to establish such interaction as a potential and effective tool in the context of drug design. Application of the halogen bond in protein systems. Halogen bonding xb is an attractive interaction between a halogen atom and an electron donor. Even though the most important noncovalent interaction is the hydrogen bond, the halogen bond has been recognized as the second most important interaction. The medicinal chemistry course adme adsorption, distribution, metabolism and excretion of drugs drugreceptor interactions development of drugs screening techniques combinatorial chemistry d.
B contact, found applications in many fields such as supramolecular chemistry, crystal engineering, medicinal chemistry, and chemical biology. Halogen bonding and weak hydrogen bonding are responsible for the binding of the host to two guests. Based on the recent structure of a microreceptor complex, we predict that 3ityr b26 engages the receptor via directional halogen bonding and halogendirected hydrogen bonding as follows. The heaviest halogens are known to form stronger halogen bonds, implying that if this trend continues down the. The persistence, particularly of the heavier halogens cl, br and i through each stage of drug development from discovery to the us fda. Regarding the binary proteinligand complexes, there are. Principles and applications of halogen bonding in medicinal. Request pdf principles and applications of halogen bonding in medicinal chemistry and chemical biology halogen bonding has been known in material. The role of halogen bonding in inhibitor recognition and. We will abbreviate halogen bonding in the following by xb, where this abbreviation is also used for the adjective halogenbonded. The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity.
Molecular interactions cambridge medchem consulting. Thermodynamic studies of halogen bonding in solution and. Halogen bonding i impact on materials chemistry and life. Crystal structure determinations of protein complexes with halogenated ligands preliminarily unveiled the functionality of halogen bonds in protein ligand recognition. Halogen bonding effect is a major driving force for the dual er. Singlecrystal crystallography unambiguously confirms the ability of the crystalline sponge to absorb and sort guests of different types. Halogen enriched fragment libraries as chemical probes for harnessing halogen bonding in fragmentbased lead discovery. Pdf halogen atoms in the modern medicinal chemistry. Now, halogen bonding the attractive interaction between an electrondeficient. Use features like bookmarks, note taking and highlighting while reading halogen bonding i. Such interactions occur regularly in the structures of many ligandprotein complexes, but have only recently been recognized in biological systems as. Oct 22, 2014 a md simulation protocol was developed to model halogen bonding in proteinligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. The effectiveness of xb in driving the formation of a multitude of supramolecular architectures having different and useful properties. The important role of halogen bond in substrate selectivity.
A medicinal chemists guide to molecular interactions. This recommendation proposes a definition for the term halogen bond, which designates a specific subset of the inter and intramolecular interactions involving a halogen atom in. Thermodynamic studies of halogen bonding in solution and application to anion recognition mohammed golam sarwar doctor of philosophy department of chemistry university of toronto 2012 abstract halogen bonding xb, the interaction between electron deficient halogen compounds and. Halogen bonding has been known in material science for decades, but until recently, halogen bonds in proteinligand interactions were largely the result of serendipitous discovery rather than rational design. Halogen bondinga novel interaction for rational drug design. Aug 23, 2008 the exact role of the halogen for binding is not always known, since often it was introduced in order to tune the hydrophobicity of the compound. Halogens in organic compounds usually are seen with one bond, three lone pairs, and a formal charge of zero. Here, the role of halogen bond in the nitrilasecatalyzed synthesis of. The ability to achieve strong molecular recognition in water is a key challenge for supramolecular chemistry. Although halogens are electronrich atoms, they act as electrophiles in these types of interactions. Halogen bonding in silico drug design, by pavel hobza, kevin riley biological halogen bonds. Computational tools to model halogen bonds in medicinal. Looking back, looking forward at halogen bonding in drug.
Halogen bonding in the crystal structures of 1,2diiodo alkenes. Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. The halogen bond, corresponding to an attractive interaction between an electrophilic region in a halogen x and a nucleophile b yielding a r. Currently she is the departmental lecturer in inorganic chemistry, college lecturer at st. Exploring halogen bonds in 5hydroxytryptamine 2b receptor. The important role of halogen bond in substrate selectivity of. Much of medicinal chemistry is based on the optimisation or reduction of interactions between a small molecule and a variety of biomolecules, this can be increasing the affinity of a ligand for a receptor or reducing affinity for some undesired offtarget interaction such as herg or cyp450. In this perspective, we provide insights into the phenomenon of halogen bonding, with special focus on its role in drug discovery. I suspect that in many instances, halogen bonding to a backbone carbonyl oxygen could be of importance. Halogen bonds are shortrange molecular interactions that are analogous to classical hydrogen bonds, except that a polarized halogen replaces the hydrogen as the acid in the lewis acidbase pair. Our results show that chloro, bromo and iodo derivatives. Current topics in medicinal chemistry, volume 7 number 14. Whereas there is so far no example of the successful application of the halogen bond in the development of new a drug, halogen bond formation between already existing drugs and their target proteins has been shown to occur in numerous cases, for example, between diclofenac and the cyclooxygenase cox2 ser530.
Current topics in medicinal chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. Halogen bonding is comparable in strength 228 to the ubiquitous hydrogen bond, however, more sensitive to steric effects because the. Toward a uniform description of hydrogen bonds and halogen. Dec 30, 2016 based on the recent structure of a microreceptor complex, we predict that 3ityrb26 engages the receptor via directional halogen bonding and halogendirected hydrogen bonding as follows. Molecular dynamics simulation of halogen bonding mimics. May 09, 2017 principles and applications of halogen bonding in medicinal chemistry and chemical biology. In both cases, a the hydrogen halogen bond acceptor is the atom, group, or molecule that donates electrons to the electron poor species hd or xd the hydrogen or halogen bond donors respectively. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a twolayer qmmm oniom methodology. Halogen bonding in the molecular recognition of thyroid. Halogen bonding is an example of a broader class of noncovalent interactions that are characterized by the electrophilic region of one of the two interacting partners. Halogen bonding in supramolecular chemistry chemical.
Meihui su state key laboratory of medicinal chemical biology, college of pharmacy, key laboratory of functional polymer materials of ministry of education, nankai university, tianjin, 300071 p. Frontiers embracing the diversity of halogen bonding motifs. Its relevance as a tool in molecular recognition has been used in different areas, such as catalysis, material science and medicinal chemistry. In this concept article, the use of halogen bond in the field of stimuli.
Request pdf principles and applications of halogen bonding in medicinal chemistry and chemical biology halogen bonding has been known in material science for decades, but until recently. A hydrogen bond often informally abbreviated h bond is a partial intermolecular bonding interaction between a lone pair on an electron rich donor atom, particularly the secondrow elements nitrogen n, oxygen o, or fluorine f, and the antibonding orbital of a bond between hydrogen h and a more electronegative atom or group. Halogen bonds have recently gained attention in life sciences and drug discovery. In recent years, halogen bonding has emerged as a tunable supramolecular synthetic tool in the design of functional liquid. Finally, the halogens fluorine, chlorine, bromine, and iodine are very important in laboratory and medicinal organic chemistry, but less common in naturally occurring organic molecules. Structurebased drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their threedimensional structures. Herein, we engineered, for the first time, an intriguing chlorosome. Halogen bonding medchembuzz medicinal chemistry blog. Taylor anion transport with halogen bonds, by stefan matile halogen bonding in silico drug design, by pavel hobza, kevin riley biological halogen bonds.
Perspectives of halogen bonding description in scoring. The other aliphatic halogen bonds are weaker, their reactivity increasing down the periodic table. The use of halogen bond is widespread in drug discovery, design, and clinical trials, but is overlooked in drug biosynthesis. Nov 17, 2014 the ability to achieve strong molecular recognition in water is a key challenge for supramolecular chemistry. Halogen bonding in the crystal structures of 1,2diiodo. The simulations confirmed the key role of halogen bonding with v5x40 and h6x55 and supported s5x43 and s5x461. Huber anion recognition in solution via halogen bonding, mark s. Halogen bonds are relevant in the field of crystal engineering3 as well as in synthetic chemistry and material science. Halogenenriched fragment libraries as chemical probes for. A detailed analysis of the interactions reveals that halogen bonding interactions are responsible for the different conformation of the molecules in the active site. Kol a r,yzand pavel hobza yinstitute of organic chemistry and biochemistry, academy of sciences of the czech. For aliphatic carbon halogen bonds, the cf bond is the strongest and usually less chemically reactive than aliphatic ch bonds. They found that an inhibitor incorporating a 4chlorophenyl moiety enhanced binding affinity by a factor of, relative to the unsubstituted analogue, and xray cocrystal.
However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. However to fully unleash the potential of xb in rational drug design fast and robust empirical methods of xb description should be developed. Halogen bonding has been known in material science for decades, but until recently, halogen bonds in protein ligand interactions were largely the result of serendipitous discovery rather than rational design. This family of attractive interactions 2 has been modeled as an electron donor interacting with the. Request pdf computational tools to model halogen bonds in medicinal chemistry the use of halogens in therapeutics dates back to the earliest days of. Comprehensive at the time treatise on how xbs can be applied for rational drug design in medicinal chemistry. Furthermore, an estimated 25% medicinal chemistry papers and patents involve the addition of halogen atoms at a late stage of the synthesis. The significance of halogen bonding in ligandreceptor. Wilcken r1, zimmermann mo, lange a, joerger ac, boeckler fm. Halogen bonding has been known in material science for decades, but until recently, halogen bonds in. The current research is the first reported molecular mechanical study of halogen bonding, the positive region centered on the halogen atom was represented by an extra. Relationships between hydrogen bonds and halogen bonds in. Extensive overview and illustration of the use and potential of halogen bonds in. Clearly, more work is required to further investigate halogen bonding in a biological context.
This journal is the royal society of chemistry 2020 comparably easy to detect complexes, in which a large electrophilic area on the halogen, typically called a shole, has been. The strengths of halogen bonds can be evaluated theoretically through quantum chemical model calculations. Whilst the overall physicochemical properties of the molecule can. The wideranging applications of the halogen bond xbond, notably in selfassembling materials and medicinal chemistry, have placed this weak intermolecular interaction in a center of great deal of attention. Examples of applications in biological medicinal chemistry and in crystal engineering are mentioned, taking note that halogen bonding can be tuned to fit various requirements, that is, strength of interaction, steric factors, and so forth.
Principles and applications of halogen bonding in medicinal chemistry and chemical biology. This protocol was then used to simulate the interactions of cathepsin l with a series of halogenated and nonhalogenated inhibitors. Xy interaction wherein x is an electrophilic halogen atom lewis acid, halogen bonding donor, d is an electron density donor lewis base, halogen bonding acceptor and y is c, n, halogen, etc. Jan 21, 2011 investigators at roche recently published a communication describing a systematic study of halogen bonding effects in proteinligand complexes of human cathepsin l hcatl. Impact on materials chemistry and life sciences topics in current chemistry book 358 kindle edition by metrangolo, pierangelo, resnati, giuseppe. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. In both cases, a the hydrogenhalogen bond acceptor is the atom, group, or molecule that donates electrons to the electron poor species hd or xd the hydrogen or halogen bond donors respectively.
Computational tools to model halogen bonds in medicinal chemistry. Quantitative assessment of halogen bonding utilizing. Although halogens are electronrich atoms, they act as. Halogen bonding involves the interaction between a halogen x and a lewis base a. Although halogens are electronrich atoms, they act as elec this is due to the presence of a significant positive charge. A chalcogen bond is an attractive interaction in the family of. A significant number of drugs and drug candidates in clinical development are halogenated structures. Halogen bondinga novel interaction for rational drug. Shing ho principles and applications of halogen bonding in medicinal chemistry, by frank m. Part ii iupac recommendations 20 definition of the halogen bond iupac recommendations 20. Here, the role of halogen bond in the nitrilasecatalyzed synthesis of ortho, meta, and parachlorophenylacetic acid was investigated. They are usually more chemically reactive than aliphatic ch bonds.
Here, we predicted the potential halogen bonding interaction between compound 2 and the 5hydroxytryptamine 2b 5ht 2b receptor and systematically assessed this interaction via structureactivity relationship analysis and molecular dynamics simulations. The recent recognition that halogen bonding xb plays important roles in the recognition and assembly of biological molecules has led to new approaches in medicinal chemistry and biomolecular engineering. Legon halogen bonding in solution, mate erdelyi unconventional motifs for halogen bonding, by kari rissanen halogen bonding in supramolecular synthesis, christer aakeroy halogen bond in synthetic organic chemistry, stefan m. It has predominantly electrostatic nature high electrostatic potential anisotropy. For a long time, insertion of halogen atoms on hit or lead compounds was predominantly performed to exploit their steric effects, through the ability of these bulk atoms to occupy the binding site of molecular targets. Her research interests are in the area of supramolecular chemistry and include exploiting halogen bonding for molecular recognition and anion templation. The correlation between the xep distance and the xy bond length was explored to determine the optimal position of the ep. Halogen bonding in a crystalline sponge inorganic chemistry.
The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligandreceptor complex by halogen bonding. Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Bonding interactions directed 2d crystalline supramolecular j. Jan 07, 20 principles and applications of halogen bonding in medicinal chemistry and chemical biology jmc 2012 posted on january 7, 20 by admetchemist wilken, r. This recommendation proposes a definition for the term halogen bond, which designates a specific subset of the inter and intramolecular interactions involving a halogen atom in a molecular entity. Definition of the halogen bond iupac recommendations 20.
A physicsbased computational protocol was then developed to further explore the opportunity of designing in halogen bonding. Database surveys further revealed a considerable number of short halogen oxygen contacts between proteins and halogenated ligands. Extending halogenbased medicinal chemistry to proteins. Halogen bonding xb is a new promising interaction pattern in medicinal chemistry. For most of the history of biochemistry and medicinal chemistry, however, halogens have been treated primarily as electronrich, lipophilic atoms that do not, in themselves, participate in specific molecular interactions that contribute to the recognition of ligands by proteins. A possible solution to overcome this problem is the use of halogen enriched fragment libraries heflibs, which consist of chemical probes that provide the. We summarize the theoretical background defining its. Feb 28, 20 principles and applications of halogen bonding in medicinal chemistry and chemical biology. Rediscovery of halogen bonds in proteinligand complexes. The wideranging applications of the halogen bond x bond, notably in selfassembling materials and medicinal chemistry, have placed this weak intermolecular interaction in a. Halogen bonding in metalorganicsupramolecular networks. Halogen bonding in supramolecular chemistry request pdf.
614 461 362 766 999 324 276 78 1594 707 343 1144 6 613 970 333 215 733 457 150 601 545 661 162 675 1419 461 1238 723 10 861 1192 1031 809 797 256 1175 258 990 918 587 1098