Certain compounds that consist of one halogen (F, Cl, Br, I, or At) linked directly to a carbon atom are generally known as organo-halogens. They are present on the earth in abundance because they are largely manufactured through biological and industrial processes. Therefore, they have been suggested as a bio-signature in the quest for life in interstellar space. Less complex halogen hydrides have been identified in comets and astrochemical sources, nevertheless the occurrence and conceivable incorporation of advanced complex halides comprising compounds such as organo-halogens into planet developing or manufacturing region is undefined. This paper reviews the contribution of halogen bonding in biological systems and explores its potential applications in pharmacology, biomaterial development, and novel motifs for nucleic acids and protein engineering.

Organo-halogen, Halides, Interstellar, Protein engineering, Halogen bonding.

Halogens, specifically the less dense (fluorine (F) and chlorine (Cl)), are broadly used components in therapeutic chemistry. Until recently, they were merely perceived as hydrophobic moieties and Lewis bases in harmony with their electronegative behavior.[1,2] Moreover, halogen bonding can occur through the involvement of side chain groups, for instance hydroxyls present in serine, tyrosine and threonine, carboxyl groups in glutamate and aspartate, sulfurs present in methionine and cysteine, nitrogen contained in histidine and also the π planes of histidine, phenylalanine, tryptophan and tyrosine. Though there are certain restrictions, this multitude of diverse interaction likelihoods in ligand to protein interactions tends to make x-bonding a very valuable tool to boost compound specificities and attractions.[3-5] In this Viewpoint, we discuss important features of the halogen bonding nature collected from a huge variety of experimental and hypothetical examinations. We offer a summary of the incidence of biologically occurring halogen bonding via systematic examination of the protein data statistics and present current instances where x-bonding has been effectively exploited for the design of ligands.

Interstellar halogens:
Usually, an extremely strong hydride bond is formed by fluorine and chlorine; the hydrogen fluoride compound is the only existing diatomic hydride. Also, hydrogen chloride ion (HCl+) is the only cation of diatomic hydride, with a cleaving energy higher than that of hydrogen gas. Theoretical research on the chemistry of chlorine-containing molecules, both in the dense and diffuse molecular mists, was carried out. In diffuse astronomical gas clouds, the prevailing ionization phase of all elements is greatly dependent on their ionization potential. Cl has an ionization potential marginally less than that of hydrogen gas, and is basically ionized separately. The chlorine ion (Cl ⁺) could react vigorously with hydrogen gas, which has been the most predominant constituent in the interstellar space.[6-8]
H2 + Cl ⁺ → HCl ⁺ + H ———————– (1)

HCl ⁺ ion is the product of this interaction, which is highly unstable as a result, it further undergoes reaction with molecular hydrogen to yield H₂Cl ⁺:
H₂ + HCl ⁺ → H₂Cl ⁺ + H ———————- (2)

The product formed in equation (2) above (H2Cl+) does not respond with molecular hydrogen; however, it is shattered by dissociative recombination and transfers a proton to carbon monoxide, both of which are potential birthplaces of hydrogen chloride (HCl).[6-8]

It stated that, prior to the unveiling of Herschel, the 35Cl and 37Cl formed from hydrogen chloride (HCl) isotope logs were the only chlorinated compounds to have been discovered in the interstellar space.[9] Though forecasts for the interaction of chlorine-containing astral molecules have acknowledged chloronium, (H2Cl+), as a reasonably profuse species that is theoretically visible. H₂Cl ⁺ is foretold to be most plentiful in those environs where the electromagnetic radiation is very strong: in the diffuse clouds region, or nigh the planes of dense clouds environs that are irradiated by near B or O stars. In such settings, ionization of atomic Cl caused by light results in a huge profusion of chlorine ions that can yield H2Cl+ and HCl+ through interaction, as shown in equations (1) and (2) above. A secondary profusion peak takes place in dense, protected regions; here, HCl turns out to be a substantial basin or reservoir of gaseous chlorine, and can yield H₂Cl ⁺, via reaction with H₃ ⁺:
H₃ ⁺ + HCl → H₂Cl ⁺ + H₂ ———————- (3)

On the other hand, the Cl exhaustion is usually large within such areas, and therefore, the overall H₂Cl ⁺ abundance is relatively small.[10,11]

Evaluation of biochemical halogen bonds:
The most wide-ranging opinion of the diversity of hydrogen bonds seen in biological systems comes from examining the protein data bank. Beginning from the first of such examination, which presented halogen bonding to the biological systems, exhaustive study of the crystalline structures in the protein data store has characterized the geometries and extended the array of acceptors accessible for the collaboration and has outlined the orthogonal and complementary associations amongst halogen and hydrogen bonds. The number of biological halogen bonds recognized in the protein data store has amplified considerably from 116 to over 600.[12,13]

Organo-halogens:
Organo-halogen compounds are well recognized for their industrial usefulness and for their injurious consequence to the ozone layer. Certain organo-halogens are naturally produced, via diverse biological and geological courses.[14] Due to their industrial and biological relationship on Earth, however, they have been suspected to be biomarkers on planetary environment where they have been identified [15] Chloromethane (CH₃Cl), is the most profuse organo-halogenated compound in the biosphere, it constitutes both synthetic and natural formation pathways. Its entire formation rate is tending about three megatons annually, with the bulk originating from biotic sources.[16] Recently, investigations of organo-chlorine molecules, comprising chloromethane, on Mars by the astronomer’s Inquisitiveness, have dared a direct linking between biology and organo-halides; one recommended source of organo-chlorine molecules on Mars is as a result of meteoritic influences.[17] This certainly nurtures the query of whether interstellar and circumstellar environs could yield organo-halogens via abiotic means, and if so, then in what amount. Our comprehension of protostellar and interstellar halide chemistry is inadequate. The only halide-bearing class detected in interstellar locations till now is diatomic and triatomic molecular halides such as HCl ⁺, H2Cl ⁺, HCl, HF, and CF ⁺.[18-22] Presently, astrochemical simulations can offer interpretation for these minor molecules with the exclusion of larger halogen-containing species. It is thus not recognized how organic interaction, and this minor halogen chemistry, combine under interstellar settings. Floro- and chloromethane were detected separately, the persistence of these organo-halides upon impact hang on the size of comet, impact angle and speed, also the thermal decomposition factors of chloromethane. Comparable to several organic molecules, we presume that the endurance or survival degree of the original chloromethane conveyed by comets might be insignificant for high speed, mid-size vertical impacting agent which could prompt temperatures rise up to 1.5 x 10 ⁴ K.[23] By disparity, sluggish impacts at scratching positions and impacts from bigger comets that can provide a shielding effect of the comet nucleus ought to increase the probability of survival. Restructuring chloromethane from disintegrated parent species owing to shock chemistry could also be important. Additional research on the impact of physics and chemistry is desirable to evaluate the net distribution.[17,20]

The succeeding gathering of chloromethane in the planetary region is solely dependent on the atmospheric constituents, such as the ultraviolet radiation (the wavelength at which CH3Cl absorbs radiation is below 203 nm), and the presence of oceans and geochemical activities. Devoted examinations are prerequisites to assess the equilibrium among CH3Cl birthplaces, i.e., cometary distribution, creation upon outgassing or impact from the interior of the planet, against sinks, for instance, atmospheric interaction with hydroxyl radicals, adsorption on solvation in ocean and rocks. In this setting, the present cometary and protostellar discoveries of organo-halogens embody a new basin of halides and a new possible birthplace of this class of molecules for exo-planets, specifically new ones that are profoundly impacted. This has implications for the anticipated use of chloromethane discovery in the atmospheric region of exoplanets as a biomarker, ever since a considerable proportion of this species seen in rocky planetary regions could have essentially been inbred from abiotic creation pathways earlier to or in the course of planet formation.[19-22]

The basis of the discovered CH3Cl is not recognized and challenging to limit without key experimental and theoretical determinations, ever since astrochemical systems do not exclude its creation, or several other organo-halides further than CH2Cl+. Between the possible creation routes, we propose that there should be minimum of two that are dependable with the detected CH₃Cl with exciting temperature of approximately 100 K and its prolonged spatial emission which includes: (a) gaseous ionic molecular chemistry with CH₄Cl ⁺ as an transitional or intermediate and (b) creation on grains via sequential halogenation and hydrogenation of carbon then sublimation follows.[23-26]

Potential chloromethane formation pathways:
Chloromethane can form in the gaseous phase starting from its protonated state (CH₄Cl ⁺), then followed by recombination of the dissociated electron to form CH₃Cl (H ⁺). CH4Cl+ could in turn be yielded from the irradiated association among CH2Cl+ and molecular hydrogen, even though the frequency of this chemical reaction is presently unidentified. The corresponding association amid H₂ and CH3 ⁺ is slow as compared to the collisional rate, approximately 10 to 14cm ³s ^-1 at a temperature of 100K, but yet operational at forming CH₅ ⁺, owing to the great profusion of hydrogen gas.[27,28] CH₂Cl ⁺ in astrochemical system is largely as a result of the interaction of CH₃ ⁺ and HCl, however CH3 ⁺ can be form via methanol (CH₃OH) destruction by either H₃ ⁺ and He⁺ ions. The detected temperature of excitation of chloromethane is comparable to the sublimation temperature required to sublime methanol. Therefore, the formation of CH₃Cl in the gaseous phase through CH₂Cl ⁺ and CH₃OH intermediated interaction is consistent with the remarks offered here.[23,25,26] The spatial range and excitation temperature of chloromethane are also reliable with the pathway of formation in the ice mantles, then sublimation follows. In icy interstellar surroundings, the majority of the molecules, with the exception of hydrogen gas, could become frozen on top of cold dust grains. However, the sequential addition of halogen and hydrogen to a carbon atom will possibly result in proficient chloromethane formation, in tandem with hydrogenated halogens and methane. Centered on experiments on chloromethane ice desorption, it can sublime at a very low temperature (70 K) within protostellar core conditions. Taking into consideration the interaction with the H₂O cold matrix, including setup, the collection of conceivable temperature of sublimation range (70 to 150K) is unchanging with the experimental excitation temperature. A thorough chemical and physical simulation is compulsory to discover whether one or both proposed pathways of formation have existed from the genesis of present methyl halogen observations.[26-28]

Biological halogen bonds:
The diversity of halogen bonds hinges on the variability of halogens observed in the biological system. There are very limited instances of naturally occurring nucleic acids and halogenated proteins, with the exception of oxidative reactions associated with them, for instance, in the case of asthma.[29] There is, on the other hand, a growing figure of halogenated nucleic acid and proteins used to assist phase crystallographic statistics, nonetheless, these adjustments are not completely nonthreatening, it has been revealed, for illustration, that halogen bonds can ease the materialization of a certain number of multi-stranded complexes of DNA, comprising the four-stranded Holliday joint.[29-31] Halogen bonds are formed largely in complexes of protein with ligands of halogen. This scenario is not unanticipated due to the predominance of halogen compounds instituted as minor metabolites, comprising an amount that is antibiotic and combined in screens to recognize inhibitors against pharmacological targets.[32] At this instance, we would deliberate on a naturally occurring halogen-containing compound known as thyroid hormones and a set of halogen inhibitors that are used as anticancer (anti-tumor) drugs to validate how halogen bonds can be advantageous in the scheme of medicine as a management technique against human ailments.[33,34]

Thyroid hormones:
The iodine-containing thyroid hormones signify a kind of naturally existing ligand where halogen bonding exhibits a key role in identification.[35] Thyroid and thyroxine hormones are related to a certain number of metabolic illnesses, which include hypercholesterolemia, diabetes, amyloidogenesis, and obesity.[34,35] The part that halogen bonds exhibit in the identification of thyroid hormones is apparent in the short Iodine-Oxygen connections observed in the structural configuration of trans-thyretin transference protein with the tetraiodothyroxine.[36]

A brominated equivalent known as 2-arylbenzoxazole (thyroid-like hormone) was seen to bind with an affinity of about 15 times higher to transthyretin above its none halogenated equivalent, and also to inhibit the materialization of transthyretin collections, which could result to a treatment remedy against mis-folding of trans-thyretin ailments.[37] Additionally, the configurations of the thyroid receptors and their hormones are observed to display connections with geometries of halogen bonding in both iodinated and brominated types.[37] It has been identified that the process of iodination was a prerequisite in the identification of thyroxine by Ribonucleic acid aptamers designated to fix this hormone.[36,38,39]

Iodo-tyrosine is formed because of thyroid hormone catabolism, after which it is processed by an enzyme (iodo-tyrosine deiodinase) to recover the halogen. The specificity of the enzyme for tyrosine equivalents trails the order of halogen polarizability (the sequence F < Cl < Br < I), signifying the participation of halogen bonding in the detection of the substrate. Recently, scientists investigated that halogen bonds are assumed to marginally lengthen the breakable Carbon-Iodine bond, a vital phase in the enzyme activity mechanism.[36] Therefore, halogen bonds seem to play vital parts in the biological study of thyroid hormones, starting from the recognition or identification by receptors to the retrieval of iodine in the course of its catabolism, and also as a necessity for preceding anabolism.[37,38]

Inhibitors against cancer targets:
Halogen comprising compounds are significant protein inhibitors, together with those that trigger carcinogenesis. Wide assessments existed on the role played by halogen bonds in recognizing numerous inhibitors against some kinds of protein kinases. Recently, two instances indicated a different iodinated inhibitor premeditated to aim the mitogen-stimulated protein kinase and a chlorine-containing inhibitor to the isoform CDC2-like kinase-1, strengthening the importance of halogen bonds in deliberating the particularity of inhibitors against certain protein kinases.[40,41]

The configurations of halogen compound inhibitors in complex with wide receptor growth factors and maltripase display that halogen bonding can be universalized to other anticancer targets. Each of the instances deliberated so far concerned halogen bonds, once more, in perception after the fact from the interaction of structural geometry or when equating the effectiveness of none halogenated to halogenated compounds against the targeted protein. Recent research shows that the halogen bonding idea can be combined at the design phase to raise the ligand affinity as prospective anticancer drugs.[39]

This review of biological halogen bonds in molecules obviously validates the potential impact of this collaboration in ligand recognition and binding, as well as in molecular folding. The reawakening of this and some other nonconventional types of connections in nucleic acids and proteins will eventually enlarge the variety of tools used for molecular design using biological molecules. The application of halogen bonding in protein engineering extends beyond stabilizing protein structures. We can foresee that halogen bonding can be present at borders to bring new protein to protein recognition sites, interactions, and even halogen bonding that is reliant on enzymatic catalysts. Organic-containing catalysts have been designed so that halogen bonding donors aid in the quickening of halide. Additionally, the halogen bond is assumed to enable iodine removal by iodothyronine deiodinase.[42,43] The halogen bond interaction aids in deteriorating the covalent connection to ease the extraction of the departing group. The addition of amino acids as halogen bond donors can therefore offer a new catalytic competence that utilizes their high directionality and tenability.

Not reported

Not reported

Corresponding Author:
Magaji Amayindi
Department of Pure and Industrial Chemistry
Bayero University Kano, Nigeria
Email: magajiamayindi@gmail.com

Co-Authors:
Joel Yakubu
Department of Community Health
Taraba State College of Health Technology, Nigeria

Jimoh Yakubu Onimisi
Department of Biochemistry
Federal University Wukari, Nigeria

Rubiyamisumma Dorcas Kaduna
Department of Science Education
Adamawa State University, Nigeria

Magaji Amayindi contributed as the author. Jimoh Yakubu Onimisi, Joel Yakubu, and Rubiyamisumma Dorcas Kaduna served as reviewers.

Not applicable

The authors declare no conflict of interest.

None

https://doi.org/10.63096/medtigo3061221

Magaji A, Joel Y, Jimoh YO, Rubiyamisumma DK. Interstellar Halogen and Biochemical Application of Halogen Bond in Living System. medtigo J Pharmacol. 2025;2(2):e3061221. doi:10.63096/medtigo3061221 Crossref