Protein Targets of Frankincense: A Reverse Docking Analysis of Terpenoids from Boswellia Oleo-Gum Resins

Background: Frankincense, the oleo-gum resin of Boswellia trees, has been used in traditional medicine since ancient times. Frankincense has been used to treat wounds and skin infections, inflammatory diseases, dementia, and various other conditions. However, in many cases, the biomolecular targets for frankincense components are not well established. Methods: In this work, we have carried out a reverse docking study of Boswellia diterpenoids and triterpenoids with a library of 16034 potential druggable target proteins. Results: Boswellia diterpenoids showed selective docking to acetylcholinesterase, several bacterial target proteins, and HIV-1 reverse transcriptase. Boswellia triterpenoids targeted the cancer-relevant proteins (poly(ADP-ribose) polymerase-1, tankyrase, and folate receptor β), inflammation-relevant proteins (phospholipase A2, epoxide hydrolase, and fibroblast collagenase), and the diabetes target 11β-hydroxysteroid dehydrogenase. Conclusions: The preferential docking of Boswellia terpenoids is consistent with the traditional uses and the established biological activities of frankincense.


Introduction
The genus Boswellia (Burseraceae) is made up of resiniferous trees and shrubs that are distributed across India, the Arabian peninsula, and Africa [1,2]. The genus is known for its aromatic terpenoid oleo-gum resin, frankincense. Frankincense has been a part of human religious ceremonies and ethnobotany for thousands of years [3]. Important frankincense-producing species include B. carteri, which grows in Somaliland and Puntland [1], B. sacra, found in Yemen, southern Oman, Somalia, and Somaliland [2], B. frereana, which is endemic to Somalia [2], B. papyrifera, primarily found in Sudan, Eritrea, and Ethiopia [4], and B. serrata, which grows primarily in India [5].
Frankincense oleo-gum resin has been used traditionally to treat wounds [6], to treat inflammatory diseases [7], for oral hygiene [8], as well as for its psychoactive effects [9,10]. The biological activities of frankincense have been attributed to its essential oils [11] and its non-volatile diterpenoids and triterpenoids [6]. Although frankincense has been used for various maladies and conditions, and numerous biological activities have been attributed to frankincense, the particular biological targets are not well established. In this work, we have carried out a reverse molecular docking study of Boswellia cembranoid diterpenoids (Figure 1), cneorubenoid diterpenoids (Figure 2), and triterpenoids ( Figure 3) against a library of 16,034 potential druggable target proteins.
The cembranoids incensole and incensole acetate were detected in the oleo-gum resin of B. papyrifera, while serratol was found in B. carteri, B. sacra, and B. serrata [12]. The

Reverse Molelcular Docking
A reverse molecular docking study was carried out on each of the Bosellia terpenoids with the sc-PDB database of druggable binding sites [32]. Each compound was examined against the 16034 protein targets contained in the sc-PDB database. Prior to docking, all solvent molecules were removed from the protein structures. Co-crystallized enzyme cofactors were retained as cofactors and co-crystallized substrates or inhibitors were retained as ligands. Molecular docking was carried out using Molegro Virtual Docker v. 6.0.1 (Molegro ApS, Aarhus, Denmark) [33] as previously reported [34]. A python script was written to generate the Molegro input files; the jobs were run as a batch from the mvd.exe command line executable. The script took the co-crystallized ligands in each protein and wrote an input file that defined the search space for that docking as a sphere centered on the ligand's center of mass. A 15-Å radius sphere was centered on the binding sites of each protein structure in order to permit each ligand to search. Standard protonation states of each protein, based on neutral pH, were used and charges were assigned based on standard templates as part of the Molegro Virtual Docker program. Each protein was used as a rigid model without protein relaxation. Flexible-ligand models were used in the docking optimizations. Different orientations of the ligands were search and ranked based on their "rerank" energy scores. A total of 100 runs for each ligand were carried out.

Conformational Analysis of Boscartol D
All calculations were carried out using Spartan'16 for Windows (Wavefunction, Inc., Irvine, CA, USA). Conformational profiles were carried out using molecular mechanics with the MMFF force field. Conformations with relative energies <20 kJ/mol were re-evaluated, with geometry optimization, using density functional theory (DFT, M06-2X/6-31G*) with a nonpolar solvent (CHCl 3 ) model.

Cembranoid Diterpenoids
The macrocyclic cembranoid diterpenoids examined in this study are shown in Figure 1. The top-binding protein targets for each of the Boswellia cembranoids are summarized in Table 1. Included in Table 1 are the median docking energies for comparison. The top binding proteins for boscartin A were acetylcholinesterase (AChE) enzymes, Torpedo californica (TcAChE) and human (HsAChE). Boscartin B docked preferentially with human N-acetylgalactosaminyltransferase (HsGTA) as well as with the bacterial targets Serratia marcescens chitinase B (SmChiB), Helicobacter pylori peptide deformylase (HpPDF), and Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (MtBioA). The proteins with the most exothermic docking for boscartin C were Escherichia coli aspartate transaminase (EcAspTA), murine acetylcholinesterase (MmAChE), and Daboia russelii (Russell's viper) phospholipase A 2 (DrPLA2). Boscartin D showed excellent docking with TcAChE (PDB 2cek, E dock = −115.3 kJ/mol) and EcAspTA. The best protein targets for boscartin E were TcAChE, HpPDF, and MtBioA. Boscartin F showed preferential docking energies with human pyruvate kinase M2 (HsPKM2), TcAChE, and HpPDF. Boscartin G showed excellent docking properties with acetylcholinesterases TcAChE and HsAChE. The proteins with the most exothermic docking energies with boscartin H were human N-acetylgalactosaminyltransferase (HsGTA), DrPLA2, SmChiB, and MmAChE. Every cembranoid ligand showed excellent docking properties to acetylcholinesterases (Table 2). Acetylcholinesterase has been identified as a target for treatment of Alzheimer's disease [35]. This is notable because frankincense (Boswellia spp.) resins have been used in Persian traditional medicine as an anti-Alzheimer's agent [36,37]. Animal models (rat) of Alzheimer's disease [38][39][40] and human clinical trials [41,42] showed beneficial effects on memory with frankincense. The lowest-energy docked pose of boscartin G with TcAChE (PDB 1e66, Figure 4A) shows the ligand to adopt the lowest-energy conformation as calculated by density functional theory at the M06-2X/6-31G*/SM8 level [31]. Key interactions between boscartin G and TcAChE are hydrophobic interactions between the ligand and aromatic amino acid side chains of Trp84, Phe330, and His440 ( Figure 4B). In addition, there are hydrogen-bonding interactions between the oxirane ring of the ligand and the phenolic -OH of Tyr121 and the C(11)-OH of the ligand and the peptide C=O of His440 ( Figure 4B). The lowest-energy docked pose of boscartin G with TcAChE (PDB 1e66, Figure 4A) shows the ligand to adopt the lowest-energy conformation as calculated by density functional theory at the M06-2X/6-31G*/SM8 level [31]. Key interactions between boscartin G and TcAChE are hydrophobic interactions between the ligand and aromatic amino acid side chains of Trp84, Phe330, and His440 ( Figure 4B). In addition, there are hydrogen-bonding interactions between the oxirane ring of the ligand and the phenolic -OH of Tyr121 and the C(11)-OH of the ligand and the peptide C=O of His440 ( Figure 4B). Boscartin A occupies the active site of TcAChE ( Figure 5A, PDB 2cek). As observed for boscartin G with TcAChE, key interactions between the docked ligand and the protein are hydrophobic interactions with Trp84, Phe330, and His440, and a hydrogen-bond between the C(11)-OH of the ligand and the His440 peptide C=O. The conformation of the lowest energy docked pose of boscartin A ( Figure 5A) is the same as the lowest-energy calculated (M06-2X/6-31G*/SM8, Figure 5B) [31] and not that found in the X-ray crystal structure [13].
Boscartin A occupies the active site of TcAChE ( Figure 5A, PDB 2cek). As observed for boscartin G with TcAChE, key interactions between the docked ligand and the protein are hydrophobic interactions with Trp84, Phe330, and His440, and a hydrogen-bond between the C(11)-OH of the ligand and the His440 peptide C=O. The conformation of the lowest energy docked pose of boscartin A ( Figure 5A) is the same as the lowest-energy calculated (M06-2X/6-31G*/SM8, Figure 5B) [31] and not that found in the X-ray crystal structure [13]. A number of bacterial proteins were targeted by Boswellia cembranoids (Table 3). Helicobacter pylori peptide deformylase (HpPDF) and Escherichia coli aspartate transaminase (EcAspTA) were particularly well targeted, while boscartin C and E and incensole oxide acetate showed remarkably exothermic docking energies. Boswellia resin extracts have shown in-vitro antibacterial activity [43][44][45], and frankincense resins have been used traditionally to treat wounds [6,46] and for oral hygiene [8]. Furthermore, B. papyrifera resin has shown activity against methicillin-resistant Staphylococcus aureus (MRSA) [47] and B. serrata resin showed activity in a clinical trial against plaque-induced gingivitis [48]. The selective targeting of bacterial proteins by Boswellia cembranoids corroborates the traditional medicinal uses and the demonstrated antibacterial activities of frankincense. A number of bacterial proteins were targeted by Boswellia cembranoids (Table 3). Helicobacter pylori peptide deformylase (HpPDF) and Escherichia coli aspartate transaminase (EcAspTA) were particularly well targeted, while boscartin C and E and incensole oxide acetate showed remarkably exothermic docking energies. Boswellia resin extracts have shown in-vitro antibacterial activity [43][44][45], and frankincense resins have been used traditionally to treat wounds [6,46] and for oral hygiene [8]. Furthermore, B. papyrifera resin has shown activity against methicillin-resistant Staphylococcus aureus (MRSA) [47] and B. serrata resin showed activity in a clinical trial against plaque-induced gingivitis [48]. The selective targeting of bacterial proteins by Boswellia cembranoids corroborates the traditional medicinal uses and the demonstrated antibacterial activities of frankincense.
The potent docking properties of Boswellia cembranoids with HpPDF are particularly noteworthy. There is a strong association between colonization of the human stomach by Helicobacter pylori and gastrointestinal illnesses such as chronic gastritis and peptic ulcers [49]. Frankincense has been used traditionally to treat stomach disturbances [4] and ulcers [46]. In addition, Boswellia extracts have been shown in clinical studies to be helpful in treating ulcerative colitis [50].
Boscartin G is the strongest binding Boswellia cembranoid ligand with HpPDF (PDB 2ew5). The lowest-energy docked pose is shown in Figure 6. Boscartin G occupies the active site of HpPDF at the same location as the co-crystallized ligand, 4-{(1E)-3-oxo-3-[(2-phenylethyl)amino]prop-1-en-1-yl}-1,2-phenylene diacetate, a cavity surrounded by Ile45, Gly95, Glu94, His138, Cys96, and Gly46 ( Figure 6B). The ligand forms two hydrogen-bonds with the peptide N-H groups of Ile45 and Gly46. The docked structure of boscartin G with HpPDF shows the same conformation ( Figure 6C) as that predicted from DFT calculations ( Figure 6D) [31]. Boscartin G is the strongest binding Boswellia cembranoid ligand with HpPDF (PDB 2ew5). The lowest-energy docked pose is shown in Figure 6. Boscartin G occupies the active site of HpPDF at the same location as the co-crystallized ligand, 4-{(1E)-3-oxo-3-[(2-phenylethyl)amino]-prop-1-en-1-yl}-1,2-phenylene diacetate, a cavity surrounded by Ile45, Gly95, Glu94, His138, Cys96, and Gly46 ( Figure 6B). The ligand forms two hydrogen-bonds with the peptide N-H groups of Ile45 and Gly46. The docked structure of boscartin G with HpPDF shows the same conformation ( Figure 6C) as that predicted from DFT calculations ( Figure 6D) [31]. Several Boswellia cembranoids showed selective docking to HIV-1 reverse transcriptase (HIV1-RT) ( Table 4). In particular, incensole oxide acetate showed excellent docking (E dock < −100 kJ/mol) to four of the seven HIV1-RT protein crystal structures. The lowest-energy docked pose of incensole oxide acetate with HIV-1 reverse transcriptase (PDB 3mee) is shown in Figure 7. Key interactions between the ligand and the protein are Tyr181, Tyr188, Leu100, Trp229, and Lys103 ( Figure 7B). Interestingly, the docking energies for the cembranoids to PDB 3lal and 3t19 are, on average, lower than for the other protein structures. The differences in docking energies can be attributed to the arrangements of the amino acid residues at the binding sites, resulting in different orientations of the docked ligands. Thus, for example, the key amino acids interacting with incensole oxide acetate in PDB 3lal are Tyr188, Leu100, Tyr181, Phe227, and Tyr318 ( Figure 7C), while PDB 3t19 had Leu100, Tyr188, Val106, Tyr318, and Tyr181 ( Figure 7D). That is, binding sites of the protein crystal structures are heavily influenced by the co-crystallized ligands. Both methanol and aqueous extracts of Boswellia carteri have demonstrated HIV-1 reverse transcriptase activity [51]. than for the other protein structures. The differences in docking energies can be attributed to the arrangements of the amino acid residues at the binding sites, resulting in different orientations of the docked ligands. Thus, for example, the key amino acids interacting with incensole oxide acetate in PDB 3lal are Tyr188, Leu100, Tyr181, Phe227, and Tyr318 ( Figure 7C), while PDB 3t19 had Leu100, Tyr188, Val106, Tyr318, and Tyr181 ( Figure 7D). That is, binding sites of the protein crystal structures are heavily influenced by the co-crystallized ligands. Both methanol and aqueous extracts of Boswellia carteri have demonstrated HIV-1 reverse transcriptase activity [51].

Cneorubenoid Diterpenoids
The cneorubenoid diterpenoids, boscartols A-I and olibanumol D, can be considered to be prenylated aromadendranes (Figure 2), and have been isolated from the oleo-gum resin of Boswellia carteri [21]. The absolute configuration of the C(15) of boscartol D was not experimentally determined C D

Cneorubenoid Diterpenoids
The cneorubenoid diterpenoids, boscartols A-I and olibanumol D, can be considered to be prenylated aromadendranes (Figure 2), and have been isolated from the oleo-gum resin of Boswellia carteri [21]. The absolute configuration of the C(15) of boscartol D was not experimentally determined [21]. Nevertheless, both diastereomers, (15R)-boscartol D and (15S)-boscartol D were used in the reverse docking. In addition, the stereochemistry of C(15) was determined theoretically using density functional theory (DFT) conformational analysis carried out at the M06-2X/6-31G* level of theory, including a non-polar (CHCl 3 ) solvent model. A complete conformational analysis of (15R)-boscartol D was carried out giving 20 low-energy conformations (E rel < 14.0 kJ/mol, accounting for 100% of the Boltzmann distribution of conformers). Similarly, conformational analysis of (15S)-boscartol D returned 13 low-energy (E rel < 13.0 kJ/mol). For each of the conformations, the H-C(15)-C(16)-H dihedral angle was determined and the corresponding vicinal coupling constants ( 3 J HH ) calculated using both the original Karplus equation [52] and the Haasnoot/Altona generalized Karplus equation that includes correction terms for the electronegativity of substituents [53]. Accounting for the Boltzmann distribution, (15R)-boscartin D is predicted to have 3 J HH of 4.3 and 5.1 Hz, respectively. The (15S)-diastereomer, on the other hand, is calculated to have 3 J HH of 6.3 and 6.5 Hz, respectively. The reported 3 J HH coupling constant was 7.6 Hz [21]. Based on the calculated 3 J HH coupling constants, the stereochemistry of boscartol D is predicted to be (15S).
The protein targets that showed the best docking properties with Boswellia cneorubenoids are listed in Table 5, along with median docking energies. The protein that was best targeted by Boswellia cneorubenoids was Bacillus anthracis nucleotide adenylyltransferase (BaNadD, PDB 3hfj) with seven of the 11 ligands showing docking energies <−120 kJ/mol. Human folate receptor β (HsFRβ, PDB 4kn0 and 4kn1) was also well targeted with 7/11 cneorubenoids with E dock < −120 kJ/mol. The strongest docking ligands were boscartol E and boscartol I, and both of these ligands targeted BaNadD (PDB 3 hfj) and HsFRβ (PDB 4kn0) very well.  Nicotinate mononucleotide adenylyltransferase (NadD) has been identified as a target for development of antibacterial agents. The excellent docking of cneorubenoids with BaNadD, along with the known antibacterial activity of frankincense [43][44][45], corroborates the traditional uses of frankincense to treat wounds [6,46].
Bacillus anthracis NadD (PDB 3hfj) is a dimeric structure with the active site at the interface of the two protein monomers (Figure 8). The active site is a hydrophobic pocket formed by Trp116A, Trp116B, Tyr112A, Tyr112B, Lys115A, and Lys115B ( Figure 8B). Human folate receptor β (HsFRβ) is overexpressed in activated macrophages associated with pathogenesis of inflammatory and autoimmune diseases [54] as well as neoplastic tissues [55]. Thus, antifolates that target folate receptors could be useful for the treatment of cancer and inflammatory diseases [56]. Clinical trials have demonstrated the encouraging results of frankincense treatment for inflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease, and collagenous colitis [57]. Boswellia cneorubenoids may be playing a role in the anti-inflammatory activity of frankincense.
The boscartols docked with HsFRβ in the folate binding site (Figure 9). The cyclopropazulane ring is surrounded by aromatic amino acids Trp187, Tyr101, Tyr76, and Phe78 ( Figure 9B). In the case of boscartol A and boscartol B, the terminal -OH group is held in place by hydrogen bonds to Ser73 and Phe78 ( Figure 9B). Human folate receptor β (HsFRβ) is overexpressed in activated macrophages associated with pathogenesis of inflammatory and autoimmune diseases [54] as well as neoplastic tissues [55]. Thus, antifolates that target folate receptors could be useful for the treatment of cancer and inflammatory diseases [56]. Clinical trials have demonstrated the encouraging results of frankincense treatment for inflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease, and collagenous colitis [57]. Boswellia cneorubenoids may be playing a role in the anti-inflammatory activity of frankincense.
The boscartols docked with HsFRβ in the folate binding site (Figure 9). The cyclopropazulane ring is surrounded by aromatic amino acids Trp187, Tyr101, Tyr76, and Phe78 ( Figure 9B). In the case of boscartol A and boscartol B, the terminal -OH group is held in place by hydrogen bonds to Ser73 and Phe78 ( Figure 9B).
(B): Boscartol I in the hydrophobic pocket formed at the interface of the two protein monomers.
Human folate receptor β (HsFRβ) is overexpressed in activated macrophages associated with pathogenesis of inflammatory and autoimmune diseases [54] as well as neoplastic tissues [55]. Thus, antifolates that target folate receptors could be useful for the treatment of cancer and inflammatory diseases [56]. Clinical trials have demonstrated the encouraging results of frankincense treatment for inflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease, and collagenous colitis [57]. Boswellia cneorubenoids may be playing a role in the anti-inflammatory activity of frankincense.
The boscartols docked with HsFRβ in the folate binding site (Figure 9). The cyclopropazulane ring is surrounded by aromatic amino acids Trp187, Tyr101, Tyr76, and Phe78 ( Figure 9B). In the case of boscartol A and boscartol B, the terminal -OH group is held in place by hydrogen bonds to Ser73 and Phe78 ( Figure 9B).

Boswellia Triterpenoids
The Boswellia triterpenoids examined in this reverse docking study are shown in Figure 3 and the target proteins with the best docking energies for each triterpenoid ligand are summarized in Table 6. The most receptive protein targets for Boswellia triterpenoids were Staphylococcus aureus multidrug binding protein (SaQacR, PDB 3bt9) with an average docking energy (Edock) of −111.
Folate receptors are overexpressed in cancer cells, presumably due to the increased requirement of cancer cells for folic acid needed in cell proliferation [71] and folate receptor-β is overexpressed in lung, liver, skin, and soft tissue tumors, as well as associated stromal cells. Folate receptors, therefore, show promise as chemotherapeutic targets for cancer and other human pathologies [72]. Three of the Boswellia triterpenoids in this study showed excellent docking properties to human folate receptor β (HsFRβ), namely dammarenediol II acetate, isofouquierol, and isofouquieryl acetate, with docking energies of −132.3, −130.4, and −137.0 kJ/mol, respectively.
Histone deacetylases (HDAC) are enzymes that remove acetyl groups from lysine residues of histones, which allow the histones to envelope DNA more tightly. Thus, HDACs can affect cell growth and differentiation and cell death [73,74]. Histone deacetylase has been recognized as a promising target for cancer chemotherapy [75,76]. Reverse docking of Boswellia triterpenoids has revealed α-elemolic acid to preferentially dock to Aquifex aeolicus histone deacetylase (AaHDAC).
Frankincense-containing formulations had been used in ancient Greece for treating various malignant tumors [77]. Frankincense has been used in the Indian traditional medicine (Ayurveda) and in Traditional Chinese Medicine (TCM) as a treatment for proliferative diseases [78]. In addition, extracts of frankincense oleo-gum resins have shown in-vitro cytotoxic activity on several human tumor-derived cell lines [58,[79][80][81], and these activities have been attributed to boswellic acids [82]. Interestingly, although β-boswellic acid [83] and 3-acetyl-11-keto-β-boswellic acid [84] have shown antineoplastic activities, this reverse-docking study did not reveal particularly notable docking properties to cancer-relevant protein targets. It may be that the boswellic acids and derivatives are targeting inflammatory pathways [85,86] or multiple targets as their mechanisms of antineoplastic activities [82,84].
Boswellia serrata is used traditionally by diabetic patients in Iran, and B. serrata supplementation has shown clinical benefit in blood lipid and glucose levels in type II diabetic patients [91,92]. Furthermore, B. serrata resin extract has been shown to prevent increase in blood glucose levels in streptozotocin-induced diabetic mice [93]. Similarly, B. glabra extracts have shown hypoglycemic effects in alloxan-induced diabetic rats [94]. The selective targeting of Guinea pig 11βHSD1 and human 11βHSD1 by Boswellia triterpenoids is consistent with the traditional use and anti-diabetic activities of Boswellia oleo-gum resin.
The oxidosqualene-hopene cyclase from the thermophilic bacterium Alicyclobacillus acidocaldarius is homologous to the human enzyme and has been crystallized with OSC inhibitors [99]. Several triterpenoid ligands, most notably ocotillyl acetate, 3β-acetoxydammar-24-ene-16β,20R-diol, and dammarenediol II acetate, docked well to AaOSC with docking energies of −144.6, −139.2, and −138.9 kJ/mol, respectively. These dammarane triterpenoids adopt the same positions in the active site of the enzyme (Figure 14). The active site of AaOSC is a hydrophobic pocket composed of Trp489, Trp169, Phe365, Ile261, Trp312, Phe601, and Tyr420. In addition, there is a hydrogen bond formed between the C(24)-OH of the ligand and the phenolic -OH of Tyr609. The structural similarities between triterpenoids and steroids are likely responsible for the docking properties of Boswellia triterpenoids to OSCs. targeting inflammatory pathways [85,86] or multiple targets as their mechanisms of antineoplastic activities [82,84].
Several Boswellia triterpenoids showed good docking properties to 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). For example, the dammarane triterpenoids 3β-acetoxy-20S,24dihydroxydammar-25-ene, 3β-acetoxydammar-24-ene-16β,20R-diol, dammarenediol II, dammarenediol II acetate, isofouquierol, and isofouquieryl acetate showed excellent docking energies with Cavia porcellus 11β-hydroxysteroid dehydrogenase type 1 (Cp11βHSD1, PDB 3lz6). These dammarane triterpenoids all occupy the same position in the active site of the enzyme, blocking access to the NADPH cofactor ( Figure 13). The docked dammaranes are sandwiched between the NADPH cofactor and hydrophobic amino acids Tyr152, Tyr98, Tyr158, Leu192, and Tyr206 ( Figure 13B). There are also close contacts, but no apparent hydrogen-bonds, with Thr197 and Asn99. 11β-Hydroxysteroid dehydrogenase type 1 mediates the interconversion of cortisone and cortisol and overexpression of 11βHSD1 can lead to metabolic disease, characterized by visceral obesity, hyperlipidemia, hypertension, glucose intolerance, insulin resistance, and type II diabetes [87,88]. Thus, inhibition of 11βHSD1 may serve as a treatment option for metabolic syndrome and type II diabetes [89,90]. Boswellia serrata is used traditionally by diabetic patients in Iran, and B. serrata supplementation has shown clinical benefit in blood lipid and glucose levels in type II diabetic patients [91,92]. Furthermore, B. serrata resin extract has been shown to prevent increase in blood glucose levels in streptozotocin-induced diabetic mice [93]. Similarly, B. glabra extracts have shown hypoglycemic effects in alloxan-induced diabetic rats [94]. The selective targeting of Guinea pig 11βHSD1 and human 11βHSD1 by Boswellia triterpenoids is consistent with the traditional use and anti-diabetic activities of Boswellia oleo-gum resin.
Oxidosqualene cyclases (OSCs) are enzymes that catalyze the cyclization of 2,3-epoxysqualene to form triterpenoids or steroids [95]. In mammals, cyclization of 2,3-epoxyaqualene leads to lanosterol, which can then be converted to cholesterol [96]. Inhibition of oxidosqualene cyclase, therefore, has emerged as a viable therapeutic option to treat hypercholesterolemia and atherosclerosis [97,98]. The oxidosqualene-hopene cyclase from the thermophilic bacterium Alicyclobacillus acidocaldarius is homologous to the human enzyme and has been crystallized with OSC A B inhibitors [99]. Several triterpenoid ligands, most notably ocotillyl acetate, 3β-acetoxydammar-24ene-16β,20R-diol, and dammarenediol II acetate, docked well to AaOSC with docking energies of −144.6, −139.2, and −138.9 kJ/mol, respectively. These dammarane triterpenoids adopt the same positions in the active site of the enzyme ( Figure 14). The active site of AaOSC is a hydrophobic pocket composed of Trp489, Trp169, Phe365, Ile261, Trp312, Phe601, and Tyr420. In addition, there is a hydrogen bond formed between the C(24)-OH of the ligand and the phenolic -OH of Tyr609. The structural similarities between triterpenoids and steroids are likely responsible for the docking properties of Boswellia triterpenoids to OSCs.

Conclusions
Numerous Boswellia terpenoid components have shown selective docking to bacterial protein targets, antineoplastic molecular targets, diabetes-relevant targets, protein targets involved in inflammatory disease conditions, and the Alzheimer's disease target acetylcholinesterase. The

Conclusions
Numerous Boswellia terpenoid components have shown selective docking to bacterial protein targets, antineoplastic molecular targets, diabetes-relevant targets, protein targets involved in inflammatory disease conditions, and the Alzheimer's disease target acetylcholinesterase. The molecular docking properties of Boswellia terpenoid components corroborate the traditional uses of frankincense, the clinical efficacy of frankincense, and the biological activities of Boswellia oleo-gum resins and components. Furthermore, the biomolecular targets identified in this work should lead to further exploration of development and improvement of inhibitors to treat these various disease states.