The Effect of Structural Modification on the Blood Brain Barrier Permeation Properties of 2 Allicin

1 The Effect of Structural Modification on the Blood Brain Barrier Permeation Properties of 2 Allicin 3 4 Abstract 5 Allicin is found in garden onion. Allicin is isolated from garlic (Allium sativum). Nutriceutical 6 allicin is an organic compound obtained from garlic. It is also obtainable from onions, and other 7 species in the family Alliaceae. It was first isolated and studied in the laboratory by Chester J. 8 Cavallito in 1944. This colourless liquid has a distinctively pungent smell. This compound 9 exhibits antibacterial and anti-fungal properties. Allicin is also the garlic's defence mechanism 10 against attacks by pests. In this experiment, we studied the effect of the substitution of a terminal 11 methyl group of allicin with hydroxyl group. The 2D structure of Allicin and its analogue were 12 designed using the ChemAxon software and saved as mrv files. The mrv files were converted 13 into SMILES strings using the OpenBabel software and pharmacokinetic parameters were 14 predicted by utilizing the SwissADME server. Results from the experiment showed that the 15 structural modification directed at the terminal methyl group of allicin converted it into a non 16 neuroactive compound with no ability to cross the blood brain barrier. 17 Keywords: Allicin; Garlic; Pharmacokinetics; Blood Brain Barrier 18 19 INTRODUCTION 20 Allicin is an organosulfur compound obtained from garlic, a species in the family Alliaceae 21 [1]. It was first isolated and studied in the laboratory by Chester J. Cavallito and John Hays 22 Bailey in 1944 [2, 3]. When fresh garlic is chopped or crushed, the enzyme alliinase 23 converts alliin into allicin, which is responsible for the aroma of fresh garlic [4]. The allicin 24 generated is unstable and quickly changes into a series of other sulfur-containing compounds 25 such as diallyl disulfide.[5] Allicin is part of a defense mechanism against attacks by pests on the 26 garlic plant.[6] 27 Allicin features the thiosulfinate functional group, R-S(O)-S-R. The compound is not present in 28 garlic unless tissue damage occurs [1], and is formed by the action of the 29 enzyme alliinase on alliin. Allicin is chiral but occurs naturally only as a racemate 30 [3]. The racemic form can also be generated by oxidation of diallyl disulfide [7]. Alliinase is 31 irreversibly deactivated below pH 3 and as such, allicin is generally not produced in the body 32 from the consumption of fresh or powdered garlic [8, 9]. Furthermore, allicin can be unstable, 33 breaking down within 16 hours at 23°C [10]. 34 Allicin is an oily, slightly yellow liquid that gives garlic its unique odor. It is 35 a thioester of sulfenic acid and is also known as allyl thiosulfinate [11]. Its biological activity can 36 be attributed to both its antioxidant activity and its reaction with thiol-containing proteins [12]. 37 In the biosynthesis of allicin (thio-2-propene-1-sulfinic acid S-allyl ester), cysteine is first 38 converted into alliin. The enzyme alliinase, which contains pyridoxal phosphate (PLP), cleaves 39 alliin, generating allysulfenic acid, pyruvate, and ammonium [12]. At room temperature 40 allysulfenic acid is unstable and highly reactive, which cause two molecules of it to 41 spontaneously combine in a dehydration reaction to form allicin [11]. 42 Produced in garlic cells, allicin is released upon disruption, producing a potent characteristic 43 scent when garlic is cut or cooked [5, 6]. Allicin has been studied for its potential to treat various 44 kinds of multiple drug resistance bacterial infections, as well as viral and fungal infections in 45 vitro, but as of 2016, the safety and efficacy of allicin to treat infections in people was unclear 46 [13]. In a small clinical trial, a daily high dose of extracted allicin (20 times the amount in a 47 garlic clove) showed effectiveness to prevent the common cold [14]. A Cochrane review found 48 this to be insufficient to draw conclusions [15]. 49 This study is aimed at investigating the effect of structural modifications on the blood brain 50 barrier permeation properties of allicin. 51 Methods 52 Ligand preparation 53 The 2D structure of allicin and its analogue were designed using the ChemAxon software [16]. 54 All designed structures were downloaded and saved as mrv files in preparation for docking. 55 File Conversion 56 Saved mrv files from the designed ligands were converted into SMILES strings (Simplified 57 Molecular Input-Line-Entry System) using the Open Babel Open Source Chemistry Toolbox. 58 Open Babel, a chemical toolbox is designed to speak many of the languages of chemical data 59 [17]. It's an open and collaborative project allowing anyone to make searches, conversions, 60 analysis, or storage data from molecular modeling, chemistry, solid state materials, biochemistry, 61 or related areas [18]. 62 Minimization of ligands 63 Allicin and its analogue were minimized using the UCSF Chimera software [19]. UCSF Chimera 64 is an extensible program for analyzing and interactively visualizing molecular structures and 65 related data which include supramolecular assemblies, density maps, alignment of sequences, 66 results from molecular docking, trajectories and conformational ensembles [20]. 67 Results and Discussion 68 Figure 1: 2D structure of Allicin 69 70 Figure 2: 2D structure of the OH analogue of Allicin 71 72 Figure 3: Drug likeness computation 73 Figure 3A: Allicin 74 75 Figure 3B: OH analogue of Allicin 76 77 Figure 4: Boiled-egg Plot 78 79 80 Molecule 1: Allicin 81 Molecule 2: OH analogue 82 The polar surface area (PSA), also known as the topological polar surface area (TPSA) of a 83 molecule is defined as the sum of all polar atoms (oxygen and nitrogen), with the inclusion of the 84 hydrogen atom attachments. The polar surface area is a metric that is often used in medicinal 85 chemistry to optimize the cell permeation ability of drugs. Molecules with a PSA value higher 86 than 140 angstroms squared are known to be poor in cell membrane penetration [21]. For 87 molecules to penetrate the blood–brain barrier (BBB) (in order to act on the central nervous 88 system receptors), the value assigned to the polar surface area must be less than 90 angstroms 89 squared [22]. The TPSA value of allicin is 61.58 angstroms, hence its ability to cross the blood 90 brain barrier as the value appeared to be lower than 90 angstroms 91 The partition coefficient between n-octanol and water (log Po/w) serves as the classical method 92 for the description of lipophilicity. The diversity of the models backing the predictors will 93 increase the accuracy in the prediction using the consensus log Po/w [23]. The lipinski’s rule 94 [24] was used as the drug likeness descriptor for the purpose of this study and the optimal 95 lipophilicity range (Log Po/w) allowed should not exceed 5. The observation from the concensus 96 lipophilicity column of figure 3A and 3B shows that allicin and its OH derivative derived are 97 within the optimal lipophilicity range and as such can be regarded as drug-like compounds. 98 Activities regarding drug development can be facilitated and made easier in cases where 99 molecules are soluble. This brings about ease in drug handling and its formulation [25]. 100 Moreover, for discovery projects that target the oral form of administration, one of the major 101 absorption property influencers the solubility of the compound [26]. Also, drugs that are 102 designed for parenteral administration requires a high solubility attribute to aid the delivery of an 103 appreciable amount of the active ingredient in smaller volumes of pharmaceutical dosage [27]. A 104 compound can be considered as soluble if the Log S value is less than 6 [25]. Allicin and its OH 105 analogue that were used for the purpose of this study, according to the column projecting the 106 solubility result in figure 3A and 3B are water soluble, implying that they might be easily 107 absorbed. 108 The nature of the gastrointestinal mucosal membrane surface area plays an important role in the 109 process of drug absorption and it has a varying and differential effect from the stomach to the 110 rectum. The physiochemical properties of the luminal content are also implicated to have an 111 influence in drug absorption process [28]. The absorption process itself is continually described 112 in terms of hypothesis of simple partition of pH, where absorption is controlled by the 113 equilibrium position between the ionized and non-ionized forms of the drug at varying 114 physiological pH values encountered in the gastrointestinal tract [29]. Allicin and its OH 115 analogue possess a high gastrointestinal absorption rate, indicating their ability to aid drug 116 bioavailability. 117 Overcoming the ability of a non neuroactive drug to cross the blood brain barrier is a major 118 challenge to be solved in the processes of designing drugs. Only neuroactive drugs are required 119 to possess the blood brain permeation attribute for functionality On the contrary, non neuroactive 120 drugs should not cross the blood brain barrier for the avoidance of psychotropic side effects [30]. 121 Blood-brain barrier permeation results from figure 3A and 3B showed that allicin lost its BBB 122 permeation properties when one of its terminal methyl groups was substituted for hydroxyl 123 group. 124 Conclusion 125 The overall result from this experiment shows the effect of structural modification on drug like 126 compounds. The substitution of a terminal methyl group (CH3) for hydroxyl group (OH) in 127 allicin converted it to a non neuroactive compound. This modified version of allicin in turn can 128 be useful in the treatment of infections that does not affect the central nervous system.

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