Biology, Medicine, & Natural Product Chemistry ISSN 2089-6514 (paper) Volume 13, Number 1, April 2024 | Pages: 239-250 | DOI: 10.14421/biomedich.2024.131.239-250 ISSN 2540-9328 (online) Commercial Incense: Compound Analysis and Its Molecular Docking Studies as Anxiolytic Agents Cintya Nurul Apsari1,*, Navista Sri Octa Ujiantari1, Zuliyati Rohmah2, Setyowati Triastuti Utami1, Artania Adnin Tri Suma1, Niar Gusnaniar3 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy; Universitas Gadjah Mada, Jl. Sekip Utara, Senolowo, Sinduadi, Yogyakarta 55281, Tel. +62-274-543120, Indonesia 2Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Jl. Teknika Sel., Sendowo, Sinduadi, Yogyakarta 55281, Tel. +62-274-580839, Indonesia. 3The Research Organization for Health, Centre for Biomedical Research, National Research and Innovation Agency (BRIN), Jl. Raya Jakarta-Bogor No.Km. 46, Pakansari, Kec. Cibinong, Kabupaten Bogor, Jawa Barat 16911, Indonesia. Corresponding author* cintyanurulapsari@ugm.ac.id Manuscript received: 29 April, 2024. Revision accepted: 20 May, 2024. Published: 28 June, 2024. Abstract In the context of Indonesian culture, incense has been traditionally utilized in various rituals. Incense possesses a calming impact and has the potential to reduce anxiety. This physiological response stems from the interplay of chemical components within incense and receptors associated with relaxation, specifically GABAA. This research aims to explore the interaction between substances found in commercially incenses with the GABAA receptors. The compounds of incense were identified through Gas Chromatography-Mass Spectrometry (GCMS) analysis. And there were 54 compounds identified from the 5 incense samples. Next, the ligands employed for docking studies were compounds predicted to traverse the blood-brain barrier (BBB). There were 31 compounds potential of crossing the blood-brain barrier (BBB). Docking results indicated that the majority of tested compounds exhibited notably lower S-scores during receptor interaction, suggesting their potential as anxiety-relieving agents. Furthermore, molecular docking outcomes highlighted that 9- Octadecenoic acid (Z)-, 2-hydroxy-1-(hydroxymethyl)ethyl ester showed the lowest S-score (-6.573). These findings imply that odorant and other volatile organic compounds (VOCs) present in incenses possess the ability to function as anxiety-reducing (anxiolytic) agents, potentially assisting in anxiety treatment. Keywords: Anxiety; aroma; fragrances; in silico; VOCs. Abbreviations: BBB: blood-brain barrier; VOCs: volatil organic compounds; GABAA: Gamma-aminobutyric acid A; GCMS: Gas Chromatography-Mass Spectrometry; RMSD: Root-Mean-Square Deviation. INTRODUCTION According to the Great Dictionary of the Indonesian Language/Kamus Besar Bahasa Indonesia [KBBI], incense is a substance such as frankincense or twigs that emits a pleasant-smelling smoke when ignited (KBBI 2023). Incense is widely utilized in religious rituals across various faiths, including Buddhism, Daoism, Confucianism (Habkirk et al. 2017), Christianity, Hinduism (Yadav et al. 2020), Roman Catholicism (Hartley et al. 2022), Judaism, Islam (Yadav et al. 2020; Faizal 2017; Karyadi 2022; Ergin 2014), as well as in the tribal and customary practices of certain nations like those in Africa (Wepener 2015; Sagrove et al. 2020), the Middle East & the Arabian Gulf region (Elsayed et al. 2016), China (Habkirk et al. 2017; Cheung 2020), Japan (Cheung 2020; Uriu et al. 2018), and India (Yadav et al. 2020). Particularly in Javanese (Indonesian) culture, incense has long been used in traditional rituals. These include engaging in traditional arts like dance, Gamelan, Kuda Lumping, Reog, and ceremony events like weddings and funerals. It can also be used in prayer and meditation practices, visits to graves and pilgrimage sites, cleaning heirlooms during jamasan ceremonies, and other purifying customs (Jamhari 2001; Nasir 2019; Perkasa et al. 2020; Yuningtyas et al. 2020; Putri 2022). Incense, frankincense, and other aromatic materials provide spiritual, psychological, and physical benefits. Incense is a proactive means of safeguarding noble ideals, customs, and ancestral wisdom, which are rich in philosophical meaning and profundity, and it is a calming and centering perfume. The rising billowing smoke symbolizes that the Almighty will hear the prayed-over or wished-for request (Wepener 2015). From a physiological standpoint, the anxiolytic qualities of some volatile substances combine to produce an environment https://doi.org/10.14421/biomedich.2024.131.239-250 240 Biology, Medicine, & Natural Product Chemistry 13 (1), 2024: 239-250 that is favorable for reflection and calm. These are conducive to the traditional practice of attaining a state of calmness. The aromatic ingredients utilized in incense production are commonly derived from plants and may encompass a range of resins, barks, seeds, roots, flowers, and mixtures of these (Coppen 1995; Yagi and Yagi 2021; Alqethami 2017; Djordjevic 2017; González- Minero et al. 2023). When breathed, the aromatic molecules bind to specific receptors, triggering a cascade of brain processes that alleviate anxiety and encourage tranquillity (Borges e Soares, 2022). This interaction is not limited to the senses; it also affects the neurotransmitter system (Sowndhararajan and Kim 2016; Masuo et al. 2021). Numerous receptors are involved in the mechanism of this anxiolytic effect, namely serotonin receptor ((5-hydroxytryptamine 1A (5-HT1A) (Heisler et al. 1998; Olivier et al. 2000) & 5-hydroxytryptamine 3 (5-HT3) (Olivier et al. 2000)), Gamma-aminobutyric acid (GABA) receptor (Nuss 2015; Islam et al. 2022), Corticosteroid receptor (GR) (Barkus et al. 2010), N- methyl-D-aspartate (NMDA) receptor (Hauger et al. 2009), corticotropin-releasing factor (CRF) receptor, cannabinoid receptor (CB1R), neurokinin-1 (NK1) receptor, melatonin (MT2) receptors, muscarinic (M1) receptors (Kaur and Singh, 2017), and nicotinic acetylcholine receptors (nAChRs), dopamine (D2/D3) receptor, orexin receptor (OX1R, OX2R) (Chellappa and Aeschbach 2022), and adenosine (A2A & A1) receptor (van Calker et al. 2019). The primary fast-inhibitory neurotransmitter receptors in the human brain are called GABAA receptors, and these receptors are the target of numerous clinically significant medications that are frequently used to treat anxiety disorders (Vashchinkina et al. 2014). Numerous studies have reported that support the efficacy of scents and their components in reducing symptoms or behaviors associated with anxiety (Hartley and McLachlan 2022). The mechanism underlying the anxiolytic effect is still unknown, mainly how the compounds interact with the receptor. An in silico method such as docking studies can be used to predict the interactions between compounds and their target receptors. Compounds contained in commercial incense will act as ligands. In this research, the incense employed consists of commercially accessible products distributed within the Yogyakarta Special Region. Therefore, this study aims to investigate how substances found in commercial incense interact with GABAA receptors. Additionally, this study is anticipated to scientifically elucidate the potential of utilizing incense and other aromatic fragrances to aid in anxiolytic therapy. MATERIALS AND METHODS Materials The materials were five incenses with different brands purchased around the Special Region of Yogyakarta, ethanol pro analysis (p.a) (Merck), analytical balance (Shimadzu ATX224), ultrasonic bath (Labocon LUC- 101), microcentrifuge (Thermo Scientific™ Fresco™ 21), microtube (Biologix), screw cap vials, and other glassware. The compound analysis required a set of Gas Chromatography Mass Spectrometry (GCMS) (Thermo Scientific TRACETM 1310 Gas Chromatography (GC) & Thermo Scientific ISQTM LT Single Quadropole Mass Spectrometer (MS)), HP-5MS UI 30M, 0.25Mm 0, 25um column (Agilent Technologies Inc, US). For in silico studies, the docking simulation was performed in Molecular Operating Environment (MOE) software (Montreal, Canada) (licensed by the Faculty of Pharmacy, Universitas Gadjah Mada) which is installed at a computer with specifications as follows Windows 10, Intel Core i7 CPU 11800H, and RAM 16 GB. Extraction of Compounds from Commercial Incense Compounds extracted from commercial incense were recovered by modifying and combining well-established research methods (Bagherian et al. 2011; West et al. 2014; Nadilah et al. 2019; Rahmanto et al. 2018). Using a mortar and stamper, incense was ground into powder. 96% ethanol (p.a.) was then used for the extraction, and the sample-to-solvent ratio was 1:100 (w/v). The extract was obtained by employing intermittent ultrasonication, involving cycles of emission for 5 minutes followed by a pause for 5 minutes, and this process was repeated until reaching a total duration of 30 minutes. After the ultrasonication procedure, maceration was carried out for 24 hours at room temperature. The extract was centrifuged at 10,000 rpm for 5 minutes to obtain clearer and entirely particle residue-free results. The supernatant was then collected in 5 mL screw-on vials. After that, the ethanolic extract was kept refrigerated (± 4 °C) for the following procedure. Identification of Compounds in Commercial Incense using GCMS GSMS analyzed the chemical constituents of incense. Ethanolic incense extract was injected into GCMS. The GC utilized a column of HP-5MS UI (Ultra Inert) 30 m, 0.25 mm, 0.25 µm (Agilent Technologies Inc, US). The chromatography system was programmed at 60 °C for 2 min, then ramped at 105 °C/min to 280 °C, and held for 8 min, with a retention time (Rt) total of 32 min. The mobile phase used was Helium UHP (He), and the flow rate was 1,0 mL/min. The injector and transfer line temperatures were 230 °C, with a split ratio of 50:1. Blood-Brain Barrier Permeability Prediction The compounds identified in the samples underwent evaluation for permeability across the blood-brain barrier (BBB) using the SwissADME server (http://www.swissadme.ch/) (Daina et al. 2017 and Rashid et al. 2022). Apsari et al. – In silico study of Incense as Anxiolytic Agents 241 Molecular Docking Ligand Preparation The ligands used for docking studies were compounds identified in the samples and could penetrate the BBB. The 3D Ligand structures were generated using the builder feature in the MOE software by entering the SMILES code of the compounds obtained from the PubChem (https://pubchem.ncbi.nlm.nih.gov/) (Kim et al. 2023). The energy minimization was applied to the compounds using the MOPAC system, employing PM3 as the potential energy function to assign charge to the compound. Subsequently, the optimized structures werearchived in a database in *.mdb format. Homology Modelling The GABAA receptor alpha-2 subunit (GABAA α2) is known to play a role in anxiolytic activity. Identification of template proteins from GABAA subunit alpha-2 in Homo sapiens (human) organisms was carried out using the SWISS-MODEL server (Waterhouse et al. 2018). The receptor sequence was obtained from the UniProt database (https://www.uniprot.org/) (The UniProt Consortium 2023) with protein code P47869. The model chosen was a model that has the highest seq value, which was Model 1 (99.78%) with the Q5RCC5 template. The GABAA α2 has been known to play a role in anxiolytic activity. Since its 3D structure is not available yet in database thus the human GABAA α2 (Homo sapiens) need to be modelled. Identification of template proteins for homology modelling the GABAA subunit alpha-2 was carried out using the SWISS-MODEL server (Waterhouse et al. 2018). The receptor sequence was obtained from the UniProt database (https://www.uniprot.org/) (The UniProt Consortium 2023) with protein code P47869. The chosen model was Model 1 which has the highest sequence value (99.78%) with the Q5RCC5 template. Protein preparations The model protein sequence was aligned with the reference protein (PDB:8BHK), which includes the native ligand (Diazepam), using MOE's protein align/superpose function. The native ligand from the reference protein was incorporated into the model protein. Subsequently, active sites were identified using MOE's site finder tool. The GABAA subunit alpha-2 protein complex derived from SWISS-MODEL was prepared using MOE's Quickprep program for structure preparation, including atomic modifications and protonation. The forcefield parameter AMBER was then used to minimize energy and assign a charge to the protein. Finally, the prepared protein was stored in PDB format (.pdb). The sequence of GABAA subunit alpha-2 protein model was aligned with the reference protein (PDB:8BHK), which includes Diazepam as the native ligand using MOE's protein align/superpose function. The native ligand from the reference protein was incorporated into the model protein. The homology model derived from SWISS-MODEL was prepared using MOE's Quickprep program for structure preparation, including atomic modifications and protonation. The forcefield parameter AMBER was then used to minimize energy and assign the charge to the protein. Finally, the prepared protein was stored in PDB format (.pdb). Pose Validation Pose validation can be done by redocking the native ligand (Diazepam) bound in the protein. Docking tool was employed with the atomic ligand designated as the active site, and set triangle matcher, induced fit, and London Dg as the parameters for placement, refinement, and scoring, respectively. RMSD (Root-Mean-Square of Deviation) is a parameter used to determines the validity of the redocking method. This parameter will evaluate the redocking process's reliability. A RMSD value of ≤ 2.0 Å indicates good or valid docking protocol (Su et al. 2018). Molecular Docking The docking method that has been validated was used to dock the test compounds in incense. The analysis of docking results involves the best pose and the best score evaluation and the interaction of those compounds amino acid residues within the protein's active site. RESULTS AND DISCUSSION This research has four primary data, i.e., 1) List of compound results from GCMS analysis, 2) Prediction of BBB Permeant, 3) Docking score, and 4) Visualization of ligand interactions with receptors. Identification of Compounds in Commercial Incense using GCMS The ethanolic extract of incense can be seen in Figure 1. The results of identification from the five incense samples are displayed in Table 1. In total, 54 compounds were identified across the five samples. Notably, incense sample B exhibited the highest number of compounds, precisely 31 compounds. Visually, incense B displayed the deepest black hue (Figure 1) and had the most pungent aroma compared to the other samples. Conversely, incense A boasted the lowest number of compound, totalling 19, among the five samples. Incense A, derived from authentic agarwood without any synthetic additives, exudes a comparatively milder aroma than incenses B, C, D, and E. Physically, the extract of incense A showcases a brownish hue (Figure 1) and has a subtle woody scent. On the other hand, Incenses C, D, and E present a golden yellow appearance in their extracts (Figure 1), with a mild floral aroma, including a mixture of flower fragrances, jasmine, and lotus, respectively. 242 Biology, Medicine, & Natural Product Chemistry 13 (1), 2024: 239-250 Figure 1. Ethanolic extract of incense. The constituents within incense consist of fragrance compounds, volatile organic compounds (VOCs), and additional ingredients utilized in incense manufacturing, such as solvents. For instance, fragrance compounds encompass dihydromyrcenol; linalol; a-terpineol; dodecanoic acid; 3-hydroxy-, (R)-lavandulyl acetate; linalyl acetate; 4-tert-butylcyclohexyl acetate; geranyl vinyl ether; 4,7-methano-1H-inden-5-ol, 3a,4,5,6,7,7a- hexahydro-, acetate ; 2,5,5,8a-tetramethyl-3,5,6,7,8,8a- hexahydro-2H-naphthalen-1-one; lilial, among others. The confirmation of fragrance compounds can be verified through databases such as the Good Scents Company's database (http://www.thegoodscentscompany.com/misc/about.htm l), which serves as an information resource for the flavor, food, and fragrance industry, and Aroma DB (https://aroma.irap.omp.eu/) (Sabbah et al. 2017). Diethyl Phthalate is also detected in incense containing synthetic fragrances (samples B, C, D, E), typically serving as solvents or diluents for fragrance agents (Api 2001). Prediction of BBB Permeant The outcomes of predictive analyses conducted through the SwissADME server are presented in Table 1. These predictions are formulated utilizing the BOILED-Egg methodology, which entails a visual assessment of human intestinal absorption relative to the molecular characteristics of small compounds plotted on the WLOGP versus TPSA graphs. The white segment within the BOILED-Egg model signifies a heightened likelihood of passive absorption within the gastrointestinal tract, while the yellow region (yolk) indicates a propensity for brain permeation (note that the yolk and white areas are not mutually exclusive) (Pavlović et al. 2023). Subsequently, compounds demonstrating positive BBB permeability are identified as ligands and subjected to docking studies with the GABAA receptor. Molecular Docking and Ligand-Receptors Interaction The homology modeling results reveal that Model 1 corresponds to a template protein derived from the Q5RCC5 protein with a sequence value of 99.78%. Pose validation yielded an RMSD value of 0.4423, indicating the docking methodology's suitability (including placement, refinement, and scoring parameters). Subsequently, a superimposed was made between the native ligand crystal and the re-docking results on the receptor (Figure 2). The docking score (S) of Diazepam was calculated as -4.3911. The docking procedure involving the test ligands and GABAA was conducted using the designated method, with 31 compounds employed as the test ligands (see Table 1). Visualization of the interaction between the best-scoring ligand and the receptor is depicted in Figure 3. Figure 2. The alignment of the native ligand crystal (purple) with the re- docking native ligand (blue). Figure 3. Visualization of 9-Octadecenoic acid (Z)-, 2-hydroxy-1- (hydroxymethyl)ethyl ester with receptor (A). Interactions within the active site (3D visualization) (B). 2D interaction with amino acid residues on the receptor. Discussion Based on the predictions from ADMET, it was identified that 31 compounds could potentially penetrate the BBB, B A Apsari et al. – In silico study of Incense as Anxiolytic Agents 243 and these were utilized as ligands for docking studies. The S-score serves as a crucial metric for assessing docking outcomes in MOE docking, indicating the affinity between receptor and ligand across various conformations (Attique et al. 2019). A lower S-score was favored, as it suggested stronger receptor interactions (Konyar et al. 2022). Evaluation of docking outcomes revealed that nearly all tested compounds exhibited lower S-scores compared to the native ligand, except for Patchouli alcohol. It can be seen in table 1, the VOCs compound 9-Octadecenoic acid (Z)-, 2-hydroxy-1- (hydroxymethyl)ethyl ester showed the lowest S-score, indicating strongest affinity for the GABAA receptor. Compounds with lower S-scores than the native ligand were presumed to possess better anxiolytic activity. Generally, VOCs are associated with either pleasant or off odors (Dudley et al. 2010). While specific aroma data for 9-Octadecenoic acid (Z)-, 2-hydroxy-1- (hydroxymethyl)ethyl ester is unavailable, its ability to evaporate and accumulate in the air. Other ligands with distinctive aromas had lower S-scores compared to native ligands (Diazepam) include Dihydromyrcenol (citrusy, floral, sweet), Linalool (floral, spicy wood), α-Terpineol (sweet lilac floral, pine-woody), (R)-lavandulyl acetate (floral, lavender-like), Linalyl acetate (floral, sweet, citric), 4-tert-Butylcyclohexyl acetate (fruity with woody undertones), Geranyl vinyl ether (floral), 4,7-methano- 1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-, acetate (floral green herbal), etc (Table 1). The interaction of 9- Octadecenoic acid (Z)-, 2-hydroxy-1- (hydroxymethyl)ethyl ester with GABAA (Figure 3b) encompasses numerous interactions, predominantly with polar amino acid residues, specifically Asn130, His129, Ser232, Tyr237, Thr234, Ser186, Tyr187, and Glu165. One hydrogen bonding was observed between hydroxyl group with Glu165. Additionally, there are hydrophobic interactions occurring with amino acid residues Pro181, Pro167, Phe127, and Ile230. These findings suggest that aromatherapy, incense, or other fragrances containing these compound types could aid in anxiety therapy. When incense is burned, these compounds transform into their oxidized forms. While this study didn't conduct GCMS analysis of the incense smoke due to limited resources, however research conducted supports the idea that aromas and other VOCs can act as anxiolytic agents. CONCLUSIONS The molecular docking outcomes indicated that the compound 9-Octadecenoic acid (Z)-, 2-hydroxy-1- (hydroxymethyl)ethyl ester exhibited the lowest S-score (-6.573) when interacting with the GABAA receptor, suggesting its promise as an anxiety-relieving agent. Furthermore, nearly all aroma compounds exhibit a lower S-score compared to Diazepam. These findings suggest that the aroma compounds present in incense possess the capability to function as anxiolytic agents and could serve as adjuncts in anxiety treatment. 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No Compounds Chemical Formula Molecular Weight Similarity Index (SI) BBB permeant Pubchem ID SMILES Aroma Score (S-score) Samples A B C D E 1 2,6-dimethyloct-7-en-2- ol (Dihydromyrcenol) C10H20O 156 891 Yes 29096 CC(CCCC(C)(C)O)C=C fresh citrus, floral, bergamot, lime -4.809 - - ✓ - ✓ 2 3,7-dimethylocta-1,6- dien-3-ol (Linalool) C10H18O 154 913 Yes 6549 CC(=CCCC(C)(C=C)O)C floral, spicy wood, somewhat resembling French lavender plants, bergamot oil or lily of the valley -4.825 - ✓ - ✓ ✓ 3 Methyl N-(N- benzyloxycarbonyl-beta- l-aspartyl)-beta-d- glucosaminide C19H26N2 O10 442 703 No 562266 COC1C(C(C(C(O1)CO)O)O)NC( =O)CC(C(=O)O)NC(=O)OCC2= CC=CC=C2 Unknown - - - - ✓ - 4 2-(4-methylcyclohex-3- en-1-yl)propan-2-ol (α- Terpineol) C10H18O 154 775 Yes 17100 CC1=CCC(CC1)C(C)(C)O slightly harsh sweet lilac, floral, pine-woody clean delicate fresh, pine, lavender pineneedle -4.820 - ✓ - - - 5 Dodecanoic acid, 3- hydroxy- C12H24O3 216 720 Yes 94216 CCCCCCCCCC(CC(=O)O)O Unknown -5.394 - - ✓ - - 6 Cholestan-3-ol, 2- methylene-, (3ß,5a)- C28H48O 400 719 No 22213932 C[C@H](CCCC(C)C)[C@H]1C C[C@@H]2[C@@]1(CC[C@H] 3[C@H]2CC[C@@H]4[C@@]3( CC(=C)[C@@H](C4)O)C)C Unknown - - ✓ - - - 7 (5-methyl-2-prop-1-en-2- ylhex-4-enyl) acetate or (R)-lavandulyl acetate C12H20O2 196 802 Yes 30247 CC(=CCC(COC(=O)C)C(=C)C) C floral, lavender- like odor -5.337 - ✓ - - - 8 3,7-dimethylocta-1,6- dien-3-yl acetate or Linalyl acetate C12H20O2 196 809 Yes 8294 CC(=CCCC(C)(C=C)OC(=O)C) C floral, sweet and citric, and additionally as minty and slightly caraway-like -5.316 - - - ✓ ✓ 9 4-tert-Butylcyclohexyl acetate C12H22O2 198 848 Yes 36081 CC(=O)OC1CCC(CC1)C(C)(C)C Fruity scent, balanced with woody undertones -4.767 - - ✓ - - 10 4-(2,2-Dimethyl-6- methylenecyclohexyl)but anal C13H22O 194 728 Yes 549482 CC1(CCCC(=C)C1CCCC=O)C Unknown -4.888 - ✓ - - - No Compounds Chemical Formula Molecular Weight Similarity Index (SI) BBB permeant Pubchem ID SMILES Aroma Score (S-score) Samples 11 Z,Z-2,5-Pentadecadien- 1-ol C15H28O 224 721 No Data 5364952 CCCCCCCCC/C=C\C/C=C\CO Unknown - - - - - ✓ 12 (2E)-1-ethenoxy-3,7- dimethylocta-2,6-diene or Geranyl vinyl ether C12H20O 180 739 Yes 5365842 CC(=CCC/C(=C/COC=C)/C)C Fruity or floral -5.140 - ✓ - - - 13 4,7-methano-1H-inden- 5-ol, 3a,4,5,6,7,7a- hexahydro-, acetate C12H16O2 192 851 Yes 98478 CC(=O)OC1CC2CC1C3C2CC=C 3 Floral green herbal -5.000 - - - - ✓ 14 1-(4-tert- Butylphenyl)propan-2- one C13H18O 190 724 Yes 6423283 CC(=O)CC1=CC=C(C=C1)C(C)( C)C Unknown -4.568 - - - ✓ - 15 2,5,5,8a-Tetramethyl- 3,5,6,7,8,8a-hexahydro- 2H-naphthalen-1-one C14H22O 206 719 Yes 585286 CC1CC=C2C(CCCC2(C1=O)C)( C)C Powdery-ionone type odours -4.850 - ✓ - - - 16 3-(4-tert-butylphenyl)-2- methylpropanal or Lilial C14H20O 204 724 Yes 228987 CC(CC1=CC=C(C=C1)C(C)(C)C )C=O Floral neroli muguet -4.745 - - ✓ ✓ - 17 Naphthalene, 2-ethoxy- C12H12O 172 722 Yes 7129 CCOC1=CC2=CC=CC=C2C=C1 Powdery, floral, naphthyl and citrus -4.481 - - - ✓ - 18 Diethyl Phthalate C12H14O4 222 957 Yes 6781 CCOC(=O)C1=CC=CC=C1C(=O )OCC Solvents/deluents -4.962 - ✓ ✓ ✓ ✓ 19 9-Octadecenoic acid, (2- phenyl-1,3-dioxolan-4- yl)methyl ester, trans- C28H44O4 444 750 No 5366356 CCCCCCCC/C=C/CCCCCCCC( =O)OCC1COC(O1)C2=CC=CC= C2 Unknown - ✓ ✓ ✓ - - 20 Methyl 5,7- hexadecadiynoate C17H26O2 262 743 Yes 14957560 CCCCCCCCC#CC#CCCCC(=O) OC Unknown -6.211 - - - - ✓ 21 2,5-Octadecadiynoic acid, methyl ester C19H30O2 290 761 Yes 42151 CCCCCCCCCCCCC#CCC#CC( =O)OC Unknown -6.079 - ✓ - - - 22 Cyclopentaneacetic acid, 3-oxo-2-pentyl-, methyl ester C13H22O3 226 777 Yes 102861 CCCCCC1C(CCC1=O)CC(=O)O C Floral and jasmine-like odor -5.645 - - - ✓ ✓ 23 (1R,3R,6S,7S,8S)- 2,2,6,8- tetramethyltricyclo[5.3.1. 03,8]undecan-3-ol or Patchouli alcohol C15H26O 222 768 Yes 10955174 C[C@H]1CC[C@@]2([C@@]3( [C@H]1C[C@H](C2(C)C)CC3) C)O Woody, patchouli, earthy -4.121 - ✓ - - - 24 (7a-Isopropenyl-4,5- dimethyloctahydroinden- 4-yl)methanol C15H26O 222 776 Yes 605599 CC1CCC2(CCCC2C1(C)CO)C(= C)C Unknown -4.614 - - - - ✓ 25 4-(3,3-Dimethyl-but-1- ynyl)-4-hydroxy-2,6,6- C15H22O2 234 741 Yes 535329 CC1=CC(CC(C1=O)(C)C)(C#CC (C)(C)C)O Unknown -5.027 - - - - ✓ No Compounds Chemical Formula Molecular Weight Similarity Index (SI) BBB permeant Pubchem ID SMILES Aroma Score (S-score) Samples trimethylcyclohex-2- enone CC1=CC(O)(CC(C)(C)C1=O)C# CC(C)(C)C 26 Benzene, 1,1'-(2-butene- 1,4-diyl)bis- C16H16 208 716 Yes 5370638 C1=CC=C(C=C1)C/C=C/CC2=C C=CC=C2 Unknown -4.917 ✓ ✓ ✓ ✓ ✓ 27 12,15-Octadecadiynoic acid, methyl ester C19H30O2 290 745 Yes 538453 CCC#CCC#CCCCCCCCCCCC( =O)OC Unknown -6.229 ✓ ✓ - - ✓ 28 N,N'- Bis(Carbobenzyloxy)- lysine methyl(ester) C23H28N2 O6 428 749 No 75487878 COC(=O)[C@H](CCCCNC(=O) OCC1=CC=CC=C1)NC(=O)OC C2=CC=CC=C2 Unknown - - - ✓ ✓ ✓ 29 Acetamide, N-methyl-N- [4-[2-acetoxymethyl-1- pyrrolidyl]-2-butynyl]- C14H22N2 O3 266 742 No 580233 CC(=O)N(C)CC#CCN1CCCC1C OC(=O)C Unknown - ✓ ✓ - - - 30 Octanal, 2- (phenylmethylene)- C15H20O 216 847 Yes 1715135 CCCCCC/C(=C/C1=CC=CC=C1 )/C=O Jasmine-like odor -5.073 - - ✓ ✓ ✓ 31 Cyclodeca[b]furan- 2,9(3H,4H)-dione, 4- (acetyloxy)- 3a,7,8,10,11,11a- hexahydro-6-methyl- 3,10-bis(methylene)-, [3ar- (3ar*,4R*,5E,11as*)]- C17H20O5 304 709 Yes 5363090 C/C/1=C\C(C2C(CC(=C)C(=O)C C1)OC(=O)C2=C)OC(=O)C Unknown -5.165 - - - - ✓ 32 Ethanone, 1- (2,3,4,7,8,8a-hexahydro- 3,6,8,8-tetramethyl-1H- 3a,7-methanoazulen-5- yl)- C17H26O 246 849 Yes 16220111 C[C@@H]1CC[C@@H]2[C@@ ]13C[C@H](C2(C)C)C(=C(C3)C (=O)C)C Warm woody amber musk -4.938 - - - - ✓ 33 "Ethanol, 2-(9- octadecenyloxy)-, (Z)- or Emulphor C20H40O2 312 801 No 5364713 CCCCCCCC/C=C\CCCCCCCC OCCO As emulsifiers, surfactants - ✓ ✓ ✓ ✓ - 34 10-Heptadecen-8-ynoic acid, methyl ester, (E)- C18H30O2 278 723 Yes 5367407 CCCCCC/C=C/C#CCCCCCCC( =O)OC Unknown -6.242 - ✓ - - - 35 Cyclopenta[g]-2- benzopyran, 1,3,4,6,7,8- hexahydro-4,6,6,7,8,8- hexamethyl- (Galaxolide) C18H26O 258 754 Yes 91497 CC1COCC2=CC3=C(C=C12)C( C(C3(C)C)C)(C)C Clean sweet musky floral woody odor -4.932 - - - ✓ ✓ 36 Benzene, 1-(1,1- dimethylethyl)-3,5- dimethyl-2,4,6-trinitro- or C12H15N3 O6 297 781 No 62329 CC1=C(C(=C(C(=C1[N+](=O)[O -])C(C)(C)C)[N+](=O)[O- ])C)[N+](=O)[O-] Musk, animalistic, earthy and woody - - ✓ - - - No Compounds Chemical Formula Molecular Weight Similarity Index (SI) BBB permeant Pubchem ID SMILES Aroma Score (S-score) Samples Musk xylene 37 "[1,1'-Bicyclopropyl]-2- octanoic acid, 2'-hexyl-, methyl ester Methyl 8-[2-(2- hexylcyclopropyl) cyclopropyl]octanoate" C21H38O2 322 785 No 552098 CCCCCCC1CC1C2CC2CCCCC CCC(=O)OC Unknown - ✓ ✓ ✓ ✓ ✓ 38 Phenethylamine, 3- benzyloxy-2-fluoro-ß- hydroxy- C15H16FN O2 261 756 No - CCCCCCC1CC1C2CC2CCCCC CCC(=O)OC Unknown - - ✓ ✓ - - 39 Hexadecane, 1,1- bis(dodecyloxy)- C40H82O2 594 721 No 41920 CCCCCCCCCCCCCCCC(OCCC CCCCCCCCC)OCCCCCCCCCC CC Unknown - ✓ ✓ ✓ - ✓ 40 2-Myristynoyl pantetheine C25H44N2 O5S 484 756 No 535560 CCCCCCCCCCCC#CC(=O)SCC NC(=O)CCNC(=O)C(C(C)(C)CO )O Unknown - - - - ✓ - 41 Cyclopropanebutanoic acid, 2-[[2-[[2-[(2- pentylcyclopropyl)methy l]cyclopropyl]methyl]cyc lopropyl]methyl]-, methyl ester C25H42O2 374 793 No 554084 CCCCCC1CC1CC2CC2CC3CC3 CC4CC4CCCC(=O)OC Unknown - ✓ ✓ ✓ - - 42 Musk ketone C14H18N2 O5 294 795 No 6669 CC1=C(C(=C(C(=C1[N+](=O)[O -])C(C)(C)C)[N+](=O)[O- ])C)C(=O)C Floral, sweet, powdery - - ✓ - - - 43 Z-(13,14- Epoxy)tetradec-11-en-1- ol acetate C16H28O3 268 806 Yes 5363633 CC(=O)OCCCCCCCCCC/C=C\ C1CO1 Unknown -5.804 ✓ ✓ ✓ ✓ ✓ 44 9-Hexadecenoic acid C16H30O2 254 827 Yes 5282745 CCCCCC/C=C/CCCCCCCC(=O) O Unknown -5.669 ✓ ✓ ✓ ✓ ✓ 45 11-Octadecenoic acid, methyl ester or Methyl vaccenate C19H36O2 296 854 No 5364432 CCCCCC/C=C/CCCCCCCCCC( =O)OC Unknown - ✓ ✓ ✓ ✓ ✓ 46 10-Octadecenoic acid, methyl ester or methyl (E)-octadec-10- enoate C19H36O2 296 816 No 5364425 CCCCCCC/C=C/CCCCCCCCC( =O)OC Unknown - - - - ✓ ✓ 47 trans-13-Octadecenoic acid C18H34O2 282 846 No 6161490 CCCC/C=C/CCCCCCCCCCCC( =O)O Unknown - ✓ ✓ ✓ - - 48 1-Heptatriacotanol C37H76O 536 820 No 537071 CCCCCCCCCCCCCCCCCCCC CCCCCCCCCCCCCCCCCO Unknown - ✓ ✓ ✓ ✓ ✓ No Compounds Chemical Formula Molecular Weight Similarity Index (SI) BBB permeant Pubchem ID SMILES Aroma Score (S-score) Samples 49 Ethyl iso-allocholate C26H44O5 436 827 No 6452096 CCOC(=O)CC[C@@H](C)[C@ H]1CC[C@@H]2[C@@]1([C@ H](C[C@H]3[C@H]2[C@@H]( C[C@H]4[C@@]3(CC[C@H](C 4)O)C)O)O)C Unknown - ✓ ✓ ✓ ✓ ✓ 50 9-Octadecenoic acid, 1,2,3-propanetriyl ester, (E,E,E)- or Trielaidin C57H104O6 884 788 No 537-39-3 CCCCCCCC/C=C/CCCCCCCC( =O)OCC(OC(=O)CCCCCCC/C= C/CCCCCCCC)COC(=O)CCCC CCC/C=C/CCCCCCCC Unknown - ✓ - - - - 51 9-Octadecenoic acid (Z)- , 2-hydroxy-1- (hydroxymethyl)ethyl ester C21H40O4 356 781 Yes 5319879 CCCCCCCC/C=C\CCCCCCCC( =O)OC(CO)CO Unknown -6.573 ✓ ✓ - ✓ - 52 Tricyclo[20.8.0.0(7,16)]t riacontane, 1(22),7(16)- diepoxy- C30H52O2 444 766 No 543764 C1CCCCC23CCCCCC45CCCC CCCCC4(O5)CCCCCC2(O3)CC C1 Unknown - ✓ ✓ - - - 53 Z-5-Methyl-6- heneicosen-11-one C22H42O 322 761 No 5363254 CCCCCCCCCCC(=O)CCC/C=C\ C(C)CCCC Unknown - ✓ ✓ - - - 54 2-[4-methyl-6-(2,6,6- trimethylcyclohex-1- enyl)hexa-1,3,5- trienyl]cyclohex-1-en-1- carboxaldehyde C23H32O 324 795 No 5363101 CC1=C(C(CCC1)(C)C)/C=C/C(= C/C=C/C2=C(CCCC2)C=O)/C Unknown - ✓ - - - ✓