INTRODUCTION:

According to WHO, 3.5 billion people in the world experience dental disease. Dental caries is found in all age groups. Caries in untreated, permanent teeth are the highest prevalence dental health problem^1-3. There are 2 billion cases of caries in permanent teeth and around 510 million cases of caries in primary teeth.

In Indonesia, the prevalence of caries based on WHO age groups reached 90.2% in the 5-year age group, 72% in the 12-year age group, 68.5% in the 15-year age group, 92.2% in the 35-44-year age group and 95% in the 65+ year age group. As many as 45% of pain cases in the orofacial region are caused by acute pulpitis⁴.

Pain is a sensory and emotional experience associated with tissue damage, which can interfere with daily activities. Bacterial infections commonly cause pain in the pulp but can also result from trauma, heat, or chemicals. Pulp pain can be relieved with compounds that have analgesic and anti-inflammatory properties One compound that has anti-inflammatory properties is ibuprofen and aspirin^5,6. Ibuprofen and aspirin are nonsteroidal anti-inflammatory drugs (NSAIDs) that are often used to reduce pain, inflammation, and fever. These drugs work by inhibiting the enzyme COX, which causes a decrease in the production of prostaglandins from arachidonic acid, a compound that can trigger inflammation and pain^7-9. Although generally safe when used in the right doses, ibuprofen can cause side effects in the form of digestive tract disorders. Inhibition of COX-1 also reduces the production of prostaglandins, which can decrease microvascular blood flow, reduce mucus secretion, and increase gastric acid production¹⁰.

Propolis is a natural resinous material collected by honeybees from various plants to build and repair their hives. It is made up of approximately 50% vegetable resins and balsams, 30% wax, 10% essential and aromatic oils, and 5% pollen and other substances, including organic matter¹¹. The chemical composition and bioactive properties of propolis can vary based on the bee species, type of source plant, geographical location, and differences in resin composition. Propolis has exhibited various biological activities such as anti-inflammatory, antioxidant, anti-fungal, antiviral, anti-cancer, antimicrobial, antiprotozoal, and antiparasitic effects. It is utilized in traditional medicine, cosmetics, food, and health¹². Propolis contains polyphenolic compounds, including flavonoids (such as quercetin) and esters (such as caffeic acid phenethyl ester (CAPE). CAPE, a powerful antioxidant component of propolis, possesses anti-inflammatory, antioxidant, and immunomodulatory properties^13,14. Research by Günay et al.¹⁵ demonstrated the role of flavonoids and Caffeic Acid Phenylethyl Ester (CAPE) as antioxidants and anti-inflammatories that promote reepithelialization and accelerate the healing process after socket extraction.

COX-2 is an enzyme involved in the synthesis of prostaglandins, which are significant in regulating inflammation, pain, and other physiological processes in the human body¹⁶. The various inflammatory mediators involved in pathological processes are prostaglandins (P.G.s), thromboxanes, and leukotrienes. Different prostaglandins are produced through the coordinated activity of the eicosanoid-forming enzyme Cyclooxygenase (COX). Scientific research drives developments aiming to improve the quality of human life and technology^17,18. Experimental research methods are categorized into in vivo, in vitro, and in silico¹⁹. These terms have Greek origins: in vivo means in life, in vitro means in a glass, and in silico means through computer simulation. In vivo refers to experiments involving whole living organisms, such as animal studies and clinical trials. In vivo tests are often conducted alongside in vitro tests to observe the overall effects of research on living subjects. In vitro refers to research techniques conducted outside the body of an organism in a controlled environment. However, these techniques sometimes struggle to replicate the exact cellular conditions in organisms, especially microbes²⁰. Meanwhile, in silico describes biological research entirely conducted through computers or computer simulations^21,22. The term was first introduced by Pedro Miramontes in 1989 at a workshop in Los Alamos, New Mexico.

In silico refers to conducting research and simulations on a computer. This approach is increasingly used in medicine and health, aided by technological advancements and access to extensive databases. In silico studies utilize open and free databases such as DNA and RNA to address medical challenges and advance medical sciences. Bioinformatics plays a key role in identifying new diseases, confirming diagnoses, and developing drugs²³. Contemporary drug discovery increasingly relies on computational approaches due to the risks associated with traditional methods²⁴.To evaluate the anti-inflammatory potential of quercetin and CAPE compounds found in propolis, researchers reviewed their specific binding affinity values to the cyclooxygenase 2 enzyme through in silico analysis. These compounds were chosen for their anti-inflammatory effects and high presence in propolis. In silico testing optimizes results from in vitro and in vivo tests^25,26. The tests involved physicochemical, molecular docking, ADMET, and PASS tests. Physicochemical tests categorize materials based on their compounds into drug-like or non-drug-like. Molecular docking tests determine binding affinity and the type of bond, ADMET tests profile the pharmacological properties of metabolite compounds, and PASS tests determine the potential activation or inactivation of metabolite compounds^27-29.

MATERIALS AND METHODS:

Research Tools:

In this in silico test, researchers used the following tools, applications, and supporting pages: Lenovo brand laptop with an Intel® Core™ i3-10110U CPU @ 2.00 GHz 1.99 GHz processor, 8.00 GB RAM, 64-bit operating system, and Windows 11 operating system with supporting software; PubChem page; RCSB PDB page; The Swiss ADME page; ProTox II website; PASS online page; PyRx App; BIOVIA Discovery Studio Visualizer app.

Research Materials:

In this in silico test, researchers used the following materials to be tested. Quercetin compound CID 5280343 has a 2-dimensional shape in .sdf format and SMILES sequence; Caffeic acid phenyl ester compound CID 5281787 has a 2-dimensional form in .sdf format and SMILES sequence; Macromolecule of cyclooxygenase 2 enzyme with 3-dimensional form in .pdb format. downloaded from protein data bank (www.rcsb.org) with PDB code: 5F19; Ibuprofen compound CID 3672 has a 2-dimensional form in .sdf format and a SMILES sequence; Aspirin compound CID 2244 has a 2-dimensional form in .sdf format and a SMILES sequence.

Research Type and Design:

This research uses a biocomputational approach (in silico). Its design uses an in silico method that consists of physicochemical tests, ADMET, PASS tests, and specific molecular docking. This study was designed to determine and analyze the binding affinity value, Pa > Pi value, and visualization of quercetin and caffeic acid phenyl ester compounds in propolis against COX-2 expression.

Analysis of physicochemical, ADMET, and PASS tests of Quercetine and CAPE compounds:

The physicochemical test results have 5 parameters with varying values. If a test compound fulfills the requirements of each parameter, it can be validated as having drug-like compound characteristics according to the Lipinski Rule of Five. Physicochemical analysis, ADMET, and PASS are carried out by comparing the values and data listed on the relevant testing website with the existing standard values.

The next step in selecting compounds with potential as drug candidates is to perform ADME (Absorption, Distribution, Metabolism, and Excretion) analysis and evaluate their toxicity properties. This is done to reduce the risk of failure in drug development. The utilization of ADMET prediction aims to evaluate drug candidates' safety and oral pharmacokinetic profile. ADME and toxicity properties are assessed through the PKCSM website. Parameters evaluated in the ADMET analysis include HIA scores and water solubility values for absorption, VDss and BBB permeability for distribution, and CYP2D6 and CYP3A4 activities for metabolism and excretion. In addition, carcinogenic and mutagenic potentials were also examined to assess toxicity aspects.

Absorption:

The absorption prediction aims to ensure that the drug candidate is effectively absorbed and permeable in the human body. The HIA value indicates the absorption of the drug in the intestine. Results with HIA values between 0-20% indicate suboptimal absorption, 20-70% indicate moderate absorption, and 70-100% indicate excellent absorption. Both quercetin and CAPE had good absorption, with values of 77% and 90% respectively. The comparison compounds, ibuprofen and aspirin, also demonstrated good absorption with values of 94% and 77% respectively.

Water solubility (log S) indicates how much a molecule can dissolve in water at 25°C. Fat-soluble drugs absorb less than water-soluble drugs, especially if taken enterally. Compounds with water solubility values less than -6 indicate a low level of solubility³⁸. As seen in Table 3, quercetin, CAPE, ibuprofen, and aspirin have water solubility values of -2.9, -3, -3.6, and -1.8, respectively. Therefore, it can be concluded that all four compounds have good absorption ability.

Distribution:

Distribution parameters analyzed include VDss values, blood-brain barrier (BBB) permeability, and central nervous system (CNS) permeability. The volume of Distribution at Steady State (VDss) describes the theoretical volume in which the total dose of the drug must be evenly distributed to reach the same concentration as blood plasma. A higher VDss value indicates that the drug is more dispersed in the tissue than in the plasma. If the VDss value is low, the drug remains in the blood circulation and has low penetration into the tissues. Conversely, if the VDss value is high, the drug leaves the blood circulation and penetrates the tissue with a higher penetration rate. According to Pires et al.³⁶, the VDss value is considered low if the logarithm of VDss is less than -0.15, while it is considered high if the logarithm of VDss is greater than 0.45. As a result of the VDss analysis, quercetin, CAPE, ibuprofen, and Aspirin had log VDss of 1.56, 0.14, -0.8, and -1.7, respectively. The test compounds quercetin and ibuprofen have high VDss values. So, it has a good distribution ability in body tissues. Meanwhile, the VDss value for the CAPE compound is low. Good results on these parameters are good for compounds with low toxicity but potentially dangerous for compounds with high toxicity levels³⁹.

The BBB, or blood-brain barrier, is a parameter used to assess how effectively a drug can cross the brain barrier and reach different areas within the brain. BBB permeability refers to a drug's ability to penetrate the brain, which can help reduce side effects and toxicity risks or increase the drug's effectiveness. The BBB is measured experimentally, and a compound can effectively penetrate the blood-brain barrier if it has a Log B.B. value greater than 0.3. Conversely, compounds with a Log B.B. value of less than -1 are considered poorly distributed. According to Nursanti⁴⁰, all five test compounds have a low BBB.

If a drug target is located in the dental or oral region and does not directly involve pain signals processed in the brain, COX-2 inhibitor compounds or drugs do not need to penetrate the blood-brain barrier (BBB) to reach their therapeutic target directly. These drugs can exert anti-inflammatory and analgesic effects at the application site or affected area without entering the central nervous system. A good score on this parameter is favorable for compounds with low toxicity but may be risky for compounds with high toxicity.

Metabolism:

The next consideration is the metabolic process. Cytochrome P (CYP) is a vital detoxifying enzyme in the body, mainly present in the liver, which performs oxidation of xenobiotics to facilitate their excretion³⁶. Therefore, assessing the ability of a compound to inhibit cytochrome P is crucial. Cytochrome P plays an important role in the metabolism of many drugs, but inhibition of CYP enzymes can significantly alter the pharmacokinetics of a drug. CYP2D6 and CYP3A4 represented cytochrome P activity in this study. CYP is a type of enzyme that plays a role in the metabolism of endogenous compounds and can catalyze oxidative biological changes in some lipophilic drug compounds and xenobiotics.

The information contained in Table 3 shows that all tested compounds have no inhibitory effect on these enzymes. The derivative compounds will likely be metabolized by these enzymes.

Excretion:

One can measure Total Clearance (CLTOT) to predict compounds' excretion. CLTOT is a combination of hepatic clearance, involving metabolism in the liver and bile, and renal clearance, which is related to excretion through the kidneys. These parameters are linked to bioavailability and are crucial for determining the appropriate dose to achieve steady-state concentrations. From Table 3, the CLTOT values of quercetin are 0.4 ml/min, CAPE is 0.5 ml/min, ibuprofen is 0.26 ml/min, and aspirin is 0.72 ml/min, which can be used to predict the speed of compound excretion. The patient's physiological conditions, such as age, weight, renal function, and liver function, also majorly affect total clearance.

Toxicity test results of compounds with Pro-Tox II and PKCSM:

Table 4. Toxicity test results

Compound	Ames	LD50	Class	Skin Sensitisation
Quercetin	Negative	159 mg/kg	3	No
CAPE	Negative	5000 mg/kg	5	No
IBP	Negative	299 mg/kg	3	Yes
ASP	Negative	250 mg/kg	3	No

In this study, we conducted toxicity tests to evaluate the potential harm of the compounds we tested. This involved determining LD50 values and toxicity classification using the ProTox II website, as well as mutagenicity testing using the Ames method as predicted through the pkCSM website. The Ames test is a method to assess whether a compound has the potential to cause mutations using bacteria⁴¹. Results of this test can be categorized as positive or negative. Positive results indicate that the compound may be mutagenic, potentially a carcinogen, and trigger mutations in cell DNA. On the other hand, negative results indicate that the compound does not have mutagenic properties⁴². Based on the data in Table 4, we found that quercetin and CAPE compounds, as well as the comparator compounds ibuprofen and aspirin, showed no mutagenic potential.

The next parameter we looked at is the prediction of toxicity as measured by the LD50 (Lethal Dose 50) value. LD50 is the dose that can cause the death of 50% of the experimental animals. LD50 is categorized into six classes: Class 1 (super toxic) for doses < 5 mg/kg, class 2 (extremely toxic) for doses of 5-50 mg/kg, class 3 (highly toxic) for doses of 50-500 mg/kg, class 4 (moderate toxicity) for doses of 0.5-5 g/kg, class 5 (mild toxicity) for doses of 5-15 g/kg, and class 6 (practically non-toxic) for doses > 15 g/kg. According to Table 5, quercetin and ibuprofen are categorized in class 3, while CAPE is in class 5, indicating that these compounds have low acute toxicity effects.

The last parameter we considered is skin sensitization, and we found that both quercetin and CAPE are negative for skin sensitization. This information can be used to set therapeutic doses, drug use doses, and lethal doses before conducting in vitro experiments and in vivo analyses.

PASS Prediction Test Results:

Table 5. PASS prediction test results

Compound	Que*	CAPE*	IBP*	ASP
Pa	0.689	0.544	0.901	0.762
Pi	0.017	0.045	0.004	0.009
∆P (Pa-Pi)	0.672	0.499	0.897	0.753

Quercetin, CAPE, and ibuprofen compounds were screened to find the most potential compounds as anti-inflammatory agents. The screening was conducted using an online database called PASS Online at the following URL: http://www.way2drug.com/PASSOnline/ , by inputting their respective canonical SMILE. The results of the PASS test provide information on the bioactivity of each compound, including the potential activity (Pa) and potential inhibitory (Pi) values. The PASS Online database can predict over 3500 biological activities, such as pharmacological effects, mechanisms of action, toxicity, side effects, metabolic enzyme interactions, compound involvement in gene expression, and more. The predictions are based on the analysis of approximately 250,000 chemical compound structures, which include drugs, drug candidates, and potentially toxic compounds^43,44.

The Pa and Pi values range from 0.000 to 1.000. If the Pa value is above 0.7, the compound has a very high level of biological activity, with results significantly similar to laboratory-scale tests. If the Pa value falls between 0.5 and 0.7, it indicates a good probability of experimental pharmacological action. If the Pa value is less than 0.5, it suggests less chance of experimental activity, but still indicates the potential for discovering new compounds.

The PASS prediction results for quercetin, CAPE, ibuprofen, and aspirin compounds can be seen in Table 5. Based on the results in Table 5, the compounds showed Pa > Pi values of 0.68 > 0.01, 0.54 > 0.04, 0.9 > 0.004, and 0.76 > 0.009, respectively. These values indicate the potential for the compounds to act as active COX-2 enzyme inhibitors. Both quercetin and CAPE have Pa values falling between 0.5 and 0.7, indicating a fairly high level of biological activity, making them bioactive substances in experimental tests and suggesting potential for development as new drug compounds with related bioactivity⁴⁵.

Molecular Docking Test Results:

Molecular docking results of quercetin, CAPE from propolis, and comparator compounds ibuprofen and aspirin against COX-2 by specific docking.

Table 6. Molecular docking test results

Target	Compounds	Binding affinity (kcal/mol)	Mode	RSMD
Target	Compounds	Binding affinity (kcal/mol)	Mode	Lower bound	Upper bound
COX-2	Quercetin	-10.0	1	0	0
	CAPE	-9.1	1	0	0
	Ibuprofen	-7.4	1	0	0
	Aspirin	-6.3	1	0	0

Visualization

Figure 1. Visualization of the bonds formed between quercetin (a), CAPE (b), and the comparator compounds ibuprofen (c) and Aspirin (d) against COX-2.

Table 7. Bond visualization results

Target Protein	Ligand	Bond Type	Amino Acids
COX-2	Quercetin	Hydrogen	Leu531, Met522, Phe 209, Leu531, Leu 534
	Quercetin	Hydrophobic	Ala527, Leu534, Val349, Ala527, Gly526, Phe381,Ala527, Leu534
	Cape	Hydrogen	Leu531,
	Cape	Hydrophobic	Val523, Phe381, Leu352, Ala527, Leu534
	Ibuprofen	Hydrogen	Leu531, Tyr385,
	Ibuprofen	Hydrophobic	Val523, Ala527, Leu352, Val523, Phe518, Val349
	Aspirin	Hydrogen	Tyr385, Leu531
	Aspirin	Hydrophobic	Ala527, Val349, Leu531

A method that can be applied to find new drug candidates from plant metabolite compounds is in silico studies using molecular docking simulations. Molecular docking simulation allows us to evaluate the interaction between the tested compounds and receptors in the human body. Molecular docking tests can provide information through interactions of metabolite compounds that act as ligands with receptors in the human body. In this in silico study, molecular docking simulation of quercetin and CAPE compounds derived from propolis with target receptor in the form of COX-2 enzyme with PDB ID 5F19 was conducted. The COX-2 enzyme represented by the PDB ID has a resolution of about 2.04 Å and is derived from homo sapiens or human organisms. The smaller the resolution value, the higher the quality of the receptor crystal resolution so that the structural representation will be closer to the original structure⁴⁶.

Molecular docking evaluated the binding affinity between the test compound and the COX-2 enzyme. This process begins with determining the position and size of the grid box to be used through the validation stage. This grid box aims to determine the receptor area at x, y, and z coordinates to identify the ligand's lowest energy conformation. The smaller the RMSD value (≤ 2) and the bond energy generated by the grid box, the more valid the repairing results are⁴⁷. The RMSD value is measured from the superposition between the original ligand and the redocking result. It is used to evaluate the accuracy of the computational method in the experimental procedure. After determining the appropriate grid box size and position, molecular docking was performed on test compounds such as quercetin, CAPE, and ibuprofen as comparison ligands and aspirin as native ligands. Aspirin is a non-steroidal anti-inflammatory drug with analgesic, antipyretic, and anti-inflammatory effects.

The parameters analyzed in molecular docking include the number of hydrogen bonds, binding affinity value, and RMSD as noted by Arwansyah et al.⁴⁸. These parameters affect the ligand's ability to bind to the receptor. The formation of more hydrogen bonds between the test ligand and the native ligand increases the likelihood of the test compound inhibiting the activity of the target protein or receptor by displacing the native ligand. Lower or negative binding affinity values indicate potential bond formation between the ligand and macromolecules⁴⁹.

In the docking results on COX-2, there are differences in binding affinity values between quercetin, CAPE, ibuprofen, and aspirin compounds. The level of binding affinity indicates the strength of the affinity of quercetin and CAPE to COX-2; the lower the binding energy, the more stable the bond formed⁵⁰. The binding affinity value of quercetin with COX-2 is -10.0 kcal/mol, while CAPE with COX-2 is -9.1 kcal/mol, ibuprofen with COX-2 is -7.2 kcal/mol, and aspirin with COX-2 is -6.3 kcal/mol. The molecular docking test results (Table 6) indicate that quercetin and CAPE compounds in propolis have good COX-2 inhibitor ability due to their lower binding affinity values compared to ibuprofen and aspirin. This suggests that the quercetin and CAPE compounds in propolis can be effective anti-inflammatory agents because they can outcompete the formation of bonds between ibuprofen and aspirin, which are common anti-inflammatory drugs, at the active site of cyclooxygenase 2⁵¹.

In addition to considering binding affinity, the value of RMSD, as noted by Du et al.⁵², is also crucial to note. Both quercetin and CAPE from propolis and comparison compounds have lower and upper limit RMSD values of 0, indicating high accuracy. Visualization using Discovery Studio 2020 Client software was then performed to display the docking results in 2D and 3D. It can visualize molecular docking results, including the amino acids that serve as the location of ligand tethering on the receptor protein. The observed interactions include hydrogen bonds, hydrophobic interactions, and electrostatic interactions within the tethering region with a distance of less than 5 angstroms (<5Å). Hydrogen bonding, as noted by Fu et al.⁵³, affects protein stability and occurs through interactions between covalently bound hydrogen atoms and electronegative atoms such as fluorine (F), nitrogen (N), and oxygen (O)⁵⁴.

The visualization of the quercetin compound revealed the formation of hydrogen bonds at amino acids LEU531, MET522, PHE 209, LEU531, and LEU 534, reinforced by several hydrophobic interactions at amino acids ALA527, LEU534, VAL349, ALA527, GLY526, PHE381, ALA527, LEU534. Similarly, the visualization of the CAPE compound indicated the formation of hydrogen bonds at LEU531, supplemented by hydrophobic interactions at amino acids VAL523, PHE381, LEU352, ALA527, and LEU534.

The results of the molecular docking test showed that quercetin and CAPE in propolis exhibit similar molecular activity to the original ligand, aspirin, as both compounds share identical peptide binding sites at the active site of the COX-2 enzyme⁵⁵. Consequently, both compounds demonstrate strong anti-inflammatory potential. Furthermore, the test ligands or compounds display the same binding site at LEU531 (LEUSIN 531) and the same hydrophobic bond at ALA527 (ALANIN 527) superimposed on the same orbital pocket. This similarity in binding sites suggests that the bound proteins possess similar properties, resulting in comparable binding affinity values and interaction modes. The existence of similar binding sites and low binding affinity of the test compounds also implies the potential of the compounds as competitive inhibitors of the COX-2 enzyme^56,57.

CONCLUSION:

The compounds quercetin and CAPE, which are found in propolis, have been identified as potential drug candidates. They have undergone physicochemical tests, ADME analysis, and toxicity prediction. These compounds have shown specific potential for inhibiting the COX-2 enzyme based on PASS prediction, docking-specific assay, and visualization. As a result, quercetin and CAPE from propolis show promise as anti-inflammatory drugs due to their ability to effectively inhibit the activity of the COX-2 enzyme. Further research using in vivo and in vitro models can be carried out to test the anti-inflammatory effects of these compounds in drug formulations derived from propolis. This data can be used as a reference for the potential development of anti-inflammatory drugs utilizing quercetin and CAPE.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

This study was partly supported by The International Research Consortium, Lembaga Penelitian dan Pengabdian Masyarakat, Universitas Airlangga, Surabaya, Indonesia in year 2024 with grant number: 171/UN3.LPPM/PT.01.03/2024.

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Received on 30.10.2024 Revised on 19.02.2025

Accepted on 21.05.2025 Published on 08.11.2025

Available online from November 13, 2025

Research J. Pharmacy and Technology. 2025;18(11):5320-5328.

DOI: 10.52711/0974-360X.2025.00767

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Parameter Name	Parameters	Description
LD50	Class I: (LD50 ≤ 5 mg/kg)	Fatal if swallowed
	Class II: (5 < LD50 ≤ 50 mg/kg)	Fatal if swallowed
	Class III: (50 < LD50 ≤ 300 mg/kg)	Toxic if swallowed
	Class IV: (300 < LD50 ≤ 2000 mg/kg)	Dangerous if swallowed
	Class V: (2000 < LD50 ≤ 5000 mg/kg).	Can be dangerous if swallowed
	Class VI: (LD50 > 5000 mg/kg).	Non-toxic
Ames Toxicity	Yes/No	It aims to determine the mutagenic potential of compounds in silico³⁰
Skin Sensitisation	Yes/No	This test was conducted to determine the sensitivity reaction on the skin in silico³⁰
Hepatoxicity	Yes/No	This test was conducted to determine the toxicity of compounds to the liver in silico³⁰

Compound	Molecular Mass (Da)	Hydrogen Bond Donor	Hydrogen Bond Acceptor	Log P
Limitations	≤500 Da	≤5	≤10	≤5
Que*	302.24 g/mol	5	7	-0.56
CAPE*	284.31 g/mol	2	4	2.62
IBP*	206.28 g/mol	1	2	3.13
ASP	152.15 g/mol	1	3	1.21

Components	Absorption		Distribution			Metabolism	Accession
	Water solubility	Intestinal absorption (human)	VDss (human)	BBB permeability	CNS permeability	CYP2D6 substrate	Total Clearance
	(log mol/L)	(% Absorbed)	(log L/kg)	(log BB)	(log PS)	(Yes/No)	(log ml/min/kg)
QUE	-2.925	77.207	1.559	-1.098	-3.065	No	0.407
CAPE	-3.031	90.637	0.139	-0.082	-2.279	No	0.547
IBP	-3.696	94.064	-0.803	0.31	-1.695	No	0.263
ASP	-1.86	76.9	-1.7	-0.3	-2.4	No	0.72