Available online on 15.11.2022 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access   Full Text Article                                                                                                                                                                                              Research Article 

ADMET-Evaluation, Pharmacokinetics, Drug-likeness and Medicinal Chemistry of GCMS Identified Bioactive Compounds of Moringa oleifera Natural-Ripened-Dried Methanolic Pod Extract (MOMPE) as a Potential Source of Natural Drug Frontrunner for Next Generation Drug Design, Development and Therapeutics

Kandeepan C.¹, Suganandam K.², Jeevalatha A.³, Kavitha N.⁴, Senthilkumar N.⁵, Sutha S.⁶, Mohamed Ali Seyed⁷, Sanyam Gandhi⁸, Ramya S.⁹, Grace Lydial Pushpalatha G¹⁰, Abraham GC.¹¹, King Immanuel J.¹², Jayakumararaj R.¹³*

¹ PG & Research Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani – 624601, TN, India

² Department of Chemistry, Velammal College of Engineering and Technology, Viraganoor, Madurai-625009, TN, India

³ Department of Zoology, GTN Arts College, Dindigul - 624005, TN, India

⁴ PG & Research Department of Chemistry, Arulmigu Palaniandavar College of Arts & Culture, Palani – 624601, TN, India

⁵ Institute of Forest Genetics & Tree Breeding (IFGTB), Indian Council of Forestry Research & Education (ICFRE), Coimbatore – 641002, TN, India 

⁶ Department of Medicinal Botany, Govt. Siddha Medical College, Palayamkottai, Tamil Nadu, India

⁷ Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, 47731, Kingdom of Saudi Arabia

⁸ Regulatory Affairs, Takeda Pharmaceuticals, Boston, MA, 02139, USA

⁹ PG Department of Zoology, Yadava College (Men), Thiruppalai - 625014, Madurai, TN, India

¹⁰ PG Department of Botany, Sri Meenakshi Government Arts College, Madurai – 625002, TN, India

¹¹ PG & Research Department of Botany, The American College, Madurai – 625002, TamilNadu, India

¹² Department of Zoology, Government Arts College, Melur – 625106, Madurai District, TN, India

¹³ Department of Botany, Government Arts College, Melur – 625106, Madurai District, TN, India

INTRODUCTION

Moringa oleifera has been used as a medicine in India since the 18^th century BC^1,2. Traditional healers used different parts of the plant as traditional medicines^3,4. The medicinal uses are numerous and have long been recognized as an Ayurvedic^2,5,6, Siddha⁷ Unani², and various other indigenous systems of medicine. Almost all parts of the plant: root, bark, gum, leaf, fruit (pods), flowers, seeds and seed oil, have been used to treat various diseases, like skin infections, swelling, anemia, asthma, bronchitis, diarrhoea, headache, joint pain, rheumatism, gout, diarrhoea, heart problems, fevers, digestive disorders, wounds, diabetes, conjunctivitis, hemorrhoids, goiter, earache, measles and smallpox in the indigenous system of medicine^8-14.

Absorption, Metabolism and Excretion of biomolecules from MO

M. oleifera has been regarded as the miraculous tree called 'tree of life' due to its immense nutritional benefits¹⁵. MO has been best studied for its nutritional benefits¹⁶. Despite noteworthy content of iron, several studies have found that M. oleifera plants have low iron bioavailability¹⁷. High polyphenolic contents of M. oleifera may exhibit a conflicting inhibitory effect on iron absorption via formation of non-bioavailable polyphenol-iron complexes¹⁸. However, formation of inhibitory complexes that lead to poor iron absorption into the body relies specifically on the structures of polyphenol compounds. In addition, it has suggested that low iron bioavailability due to high phytic acid content; removal of phytic acid may improve bioavailability¹⁸. Similarly, M. oleifera is rich in minerals and vitamins, MO has high calcium content, but presence of oxalic acid in leaves interfere with calcium absorption¹⁹. MO leaves contain oxalate, which has been suggested as cause of reduced calcium bioavailability. Bioavailability effects caused by the presence of phytic and oxalic acid in dietary consumption have ironically labeled them as anti-nutritional factors. Vit-A, Vit-B are the most significant among reported nutrients from M. oleifera leaves and the most abundant natural sources for β-carotene and pro-vitamin A carotenoid. In vivo and in vitro studies indicate that natural vitamin from M. oleifera are readily bioavailable with good absorption of nutritional values. M. oleifera include all essential amino acids amenable to efficient absorption of high protein content. Studies suggest that amino acids or proteins in M. oleifera are highly digestible that equates to its bioavailability²⁰.

Toxicology and Safety aspects of biomolecules from MO

Toxicity and safety assessment of M. oleifera has been described in many studies, with no significant adverse effects of its consumption based on human studies have been reported. Most of the in vitro studies involved the use of normal human cell lines and cancerous cell lines as the indices for the safety and toxicity of M. oleifera extract treatment²¹. Cytotoxicity assessment of aqueous seed extract of M. oleifera indicated that 2000 mg/kg dose of administration in mice, no systemic toxicity was observed with no significant changes^22,23 in erythrocytes, platelets, hemoglobin, and hematocrit observed for the control group²⁴. Acute toxicity/ LD₅₀ of 70% ethanolic M. oleifera leaf extracts injected intraperitoneally with 150 mg/mL of extracts at interval 5 min until mortality was reached indicated that lethal dose for AT was 6616.67 mg/kg for rats and 26,043.67 mg/kg for rabbits²⁵ confirmed by histopathology observation concluded that ethanolic extracts of M. oleifera leaves have minimum toxicity if given within appropriate doses and ranges of time.

Blood samples was collected for biochemical analysis of acute oral toxicity of aqueous-methanolic leaf extract on female rats as biomarkers of liver dysfunction found that, at a 2000 mg/kg oral dose, levels of aspartate aminotransferase (AST) increased significantly, total bilirubin and a non-significant decrease in the levels of alanine aminotransferase (ALT) as compared to control. In addition, postmortem analysis showed a non-significant increase in hepatic index (liver to body weight ratio) with mild distortions in liver cells¹⁸. Studies on AST, ALT and ALP with both seed and leaf extracts of MO indicated that both are safe for consumption in appropriate doses with enhanced immunity and offer hepatoprotective potential²⁶. 

Recent review by Azlan et al¹⁸ highlights that clinical trials performed on humans are essential to investigate behavioral, medical or surgical intervention of targeted properties of biomolecules. Literature data on M. oleifera-related clinical trials showed that there are approximately 25 interventional studies that have been registered under registry of clinical trials, of which 15 have been completed, and 10 on-going. Likewise, among the trials, 17 are supplementation diets of Moringa, 6 drug interventions, and 2 are Moringa-based mouthwashes for orthodontic application¹⁸.

MATERIAL AND METHODS

In silico Drug-Likeliness and Bioactivity Prediction

Drug likeliness and bioactivity of selected molecule was analyzed using the Molinspiration server (http://www.molinspiration.com). Molinspiration tool is cheminformatics software that provides molecular properties as well as bioactivity prediction of compounds²⁷. In this analysis, there are two important factors, viz., lipophilicity level (log P) and polar surface area (PSA) directly associated with pharmacokinetic properties (PK) of compounds⁹. In Molinspiration-based bioactivity analysis, the calculation of the bioactivity score of compounds toward GPCR ligands, ion channel modulators, kinase inhibitors, nuclear receptor ligands, protease inhibitors, and other enzyme targets were analyzed by Bayesian statistics. This was carried out for G protein-coupled receptors (GPCR), ion channels, kinases, nuclear hormone receptors, proteases.

In silico ADMET Analysis

SwissADME is a web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, druglikeness and medicinal chemistry friendliness, among which in-house proficient methods such as iLOGP (a physics-based model for lipophilicity) or BOILED-Egg (graphical classification model for gastrointestinal absorption and brain access). Further, it enables ADME-related calculation for multiple molecules, allowing chemical library analysis and efficient lead optimization²⁸. PK properties, such as Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET), of fatty acids were predicted using admerSAR v2.0 server (http://lmmd.ecust.edu.cn/admetsar2/) and the admerSAR server is an open-source computational tool for prediction of ADMET properties of compounds, which makes it a practical platform for drug discovery and other pharmacological research^29,30.

In ADMET analysis, absorption (A) of good drugs depends on factors such as membrane permeability³¹ [designated by colon cancer cell line (Caco-2)], human intestinal absorption (HIA)³², and status of either P-glycoprotein substrate or inhibitor³³. Distribution (D) of drugs mainly depends on the ability to cross blood-brain barrier (BBB)³⁴. The metabolism (M) of drugs is calculated by the CYP, MATE1, and OATP1B1-OATP1B3 models³⁵. Excretion (E) of drugs is estimated based on the renal OCT substrate. Toxicity (T) of drugs is predicted on Human Ether-A-Go-Go related gene inhibition, carcinogenic status, mutagenic status, and acute oral toxicity³⁶. Pharmacokinetic prediction comprised of solubility (logS), partition coefficient (clogP), drug likeness and molecular weight properties³⁷. The drug score was calculated by combining with drug likeness, cLogP, logS, molecular weight and toxicity risks in one handy value than may be used to judge the compound's overall potential to qualify for a drug. https://www.organic-chemistry.org/prog/peo/ 

RESULTS AND DISCUSSION

                  Previous studies^38-49 indicates that the successful exploitation of plant based natural products depends on the identification, isolation, purification and ADMET characterization followed by clinical trials before its launch in the market. Phytochemical screening and GCMS analysis revealed the presence of 12 compounds namely - 7-Octadecyne, 2-methyl- (C₁₉H₃₆); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); 6,9,12,15-Docosatetraenoic acid, me (C₂₃H₃₈O₂); Cyclohexanol, 5-methyl-2-(1-methylethyl)- (C₁₀H₂₀O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); Palmitic acid vinyl ester (C₁₈H₃₄O₂); .gamma.-Tocopherol (C₂₈H₄₈O₂); Vitamin E (C₂₉H₅₀O₂); Cholesta-7,9(11)-dien-3-ol, 4,4-dim (C₂₉H₄₈O); gamma.-Sitosterol (C₂₉H₅₀O); Stigmasta-5,24(28)-dien-3-ol, (3.beta.,24Z)- (C₂₉H₄₈O).¹⁴

ADMET informatics of 7-Octadecyne, 2-methyl- (M1)

MW of M1 = 264.49; # Heavy atoms in M1 = 19; # aromatic Heavy atoms in M1 = 0; Fraction Csp3 in M1 = 0.89; # rotatable bonds in M1 = 12; # H-bond acceptors in M1 = 0; # H-bond donors in M1 = 0; Molar refractivity in M1 = 91.61; Topological polar surface area of M1 = 0; Log Po/w value for M1 = 5.25; The octanol–water partition coefficient (XLOGP3) for M1 = 9.04; lipophilicity of large molecules (WLOGP) for M1 = 6.82; Moriguchi octanol-water partition coefficient (MLOGP) for M1 = 7.01; Silicos-IT Log P in M1 = 7.04; Consensus Log P in M1 = 7.03; ESOL Log S in M1 = -6.38; ESOL Solubility (mg/ml) for M1 = 1.09E-04; ESOL Solubility (mol/l) for M1 = 4.14E-07; ESOL Class value for M1 = PS; Ali Log S in M1 = -8.93; Ali Solubility (mg/ml) for M1 = 3.09E-07; Ali Solubility (mol/l) for M1 = 1.17E-09; Ali Class value for M1 = PS; Silicos-IT LogSw in M1 = -6.44; Silicos-IT Solubility (mg/ml) for M1 = 9.67E-05; Silicos-IT Solubility (mol/l) for M1 = 3.66E-07; Silicos-IT class value for M1 = PS; GI absorption by M1 = Low; BBB permeant in M1 = No; Pgp substrate in M1 = No; CYP1A2 inhibitor - M1 = Yes; CYP2C19 inhibitor - M1 = No; CYP2C9 inhibitor - M1 = No; CYP2D6 inhibitor - M1 = No; CYP3A4 inhibitor - M1 = No; log Kp (cm/s) for M1 = -1.49; Lipinski’s Rule violations by M1 = 1; Ghose’s Rule violations by M1 = 1; Veber’s Rule violations by M1 = 1; Egan’s Rule violations by M1 = 1; Muegge’s Rule violations by M1 = 2; PAINS # alerts for M1 = 0; Brenk # alerts for M1 = 1; Leadlikeness violations by M1 = 2; SA Score in M1 = 4.83; Bioavailability Score in M1 = 0.55 (Fig.1a; Table 2-6). 

ADMET informatics of 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (M2)

MW of M2 = 296.53; # Heavy atoms in M2 = 21; # aromatic Heavy atoms in M2 = 0; Fraction Csp3 in M2 = 0.9; # rotatable bonds in M2 = 13; # H-bond acceptors in M2 = 1; # H-bond donors in M2 = 1; Molar refractivity in M2 = 98.94; Topological polar surface area of M2 = 20.23; Log Po/w value for M2 = 4.66; The octanol–water partition coefficient (XLOGP3) for M2 = 8.19; lipophilicity of large molecules (WLOGP) for M2 = 6.36; Moriguchi octanol-water partition coefficient (MLOGP) for M2 = 5.25; Silicos-IT Log P in M2 = 6.57; Consensus Log P in M2 = 6.21; ESOL Log S in M2 = -5.98; ESOL Solubility (mg/ml) for M2 = 3.10E-04; ESOL Solubility (mol/l) for M2 = 1.05E-06; ESOL Class value for M2 = MS; Ali Log S in M2 = -8.47; Ali Solubility (mg/ml) for M2 = 9.94E-07; Ali Solubility (mol/l) for M2 = 3.35E-09; Ali Class value for M2 = PS; Silicos-IT LogSw in M2 = -5.51; Silicos-IT Solubility (mg/ml) for M2 = 9.06E-04; Silicos-IT Solubility (mol/l) for M2 = 3.05E-06; Silicos-IT class value for M2 = MS; GI absorption by M2 = Low; BBB permeant in M2 = No; Pgp substrate in M2 = Yes; CYP1A2 inhibitor - M2 = No; CYP2C19 inhibitor - M2 = No; CYP2C9 inhibitor - M2 = Yes; CYP2D6 inhibitor - M2 = No; CYP3A4 inhibitor - M2 = No; log Kp (cm/s) for M2 = -2.29; Lipinski’s Rule violations by M2 = 1; Ghose’s Rule violations by M2 = 1; Veber’s Rule violations by M2 = 1; Egan’s Rule violations by M2 = 1; Muegge’s Rule violations by M2 = 2; PAINS # alerts for M2 = 0; Brenk # alerts for M2 = 1; Leadlikeness violations by M2 = 2; SA Score in M2 = 4.3; Bioavailability Score in M2 = 0.55 (Fig.1b; Table 2-6).

ADMET informatics of 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (M3)

MW of M3 = 296.53; # Heavy atoms in M3 = 21; # aromatic Heavy atoms in M3 = 0; Fraction Csp3 in M3 = 0.9; # rotatable bonds in M3 = 13; # H-bond acceptors in M3 = 1; # H-bond donors in M3 = 1; Molar refractivity in M3 = 98.94; Topological polar surface area of M3 = 20.23; Log Po/w value for M3 = 4.66; The octanol–water partition coefficient (XLOGP3) for M3 = 8.19; lipophilicity of large molecules (WLOGP) for M3 = 6.36; Moriguchi octanol-water partition coefficient (MLOGP) for M3 = 5.25; Silicos-IT Log P in M3 = 6.57; Consensus Log P in M3 = 6.21; ESOL Log S in M3 = -5.98; ESOL Solubility (mg/ml) for M3 = 3.10E-04; ESOL Solubility (mol/l) for M3 = 1.05E-06; ESOL Class value for M3 = MS; Ali Log S in M3 = -8.47; Ali Solubility (mg/ml) for M3 = 9.94E-07; Ali Solubility (mol/l) for M3 = 3.35E-09; Ali Class value for M3 = PS; Silicos-IT LogSw in M3 = -5.51; Silicos-IT Solubility (mg/ml) for M3 = 9.06E-04; Silicos-IT Solubility (mol/l) for M3 = 3.05E-06; Silicos-IT class value for M3 = MS; GI absorption by M3 = Low; BBB permeant in M3 = No; Pgp substrate in M3 = Yes; CYP1A2 inhibitor - M3 = No; CYP2C19 inhibitor - M3 = No; CYP2C9 inhibitor - M3 = Yes; CYP2D6 inhibitor - M3 = No; CYP3A4 inhibitor - M3 = No; log Kp (cm/s) for M3 = -2.29; Lipinski’s Rule violations by M3 = 1; Ghose’s Rule violations by M3 = 1; Veber’s Rule violations by M3 = 1; Egan’s Rule violations by M3 = 1; Muegge’s Rule violations by M3 = 2; PAINS # alerts for M3 = 0; Brenk # alerts for M3 = 1; Leadlikeness violations by M3 = 2; SA Score in M3 = 4.3; Bioavailability Score in M3 = 0.55 (Fig.1c; Table 2-6). 

ADMET informatics of 6,9,12,15-Docosatetraenoic acid, me (M4)

MW of M4 = 332.52; # Heavy atoms in M4 = 24; # aromatic Heavy atoms in M4 = 0; Fraction Csp3 in M4 = 0.59; # rotatable bonds in M4 = 16; # H-bond acceptors in M4 = 2; # H-bond donors in M4 = 1; Molar refractivity in M4 = 107.74; Topological polar surface area of M4 = 37.3; Log Po/w value for M4 = 4.99; The octanol–water partition coefficient (XLOGP3) for M4 = 7.94; lipophilicity of large molecules (WLOGP) for M4 = 7; Moriguchi octanol-water partition coefficient (MLOGP) for M4 = 5.2; Silicos-IT Log P in M4 = 7.17; Consensus Log P in M4 = 6.46; ESOL Log S in M4 = -5.85; ESOL Solubility (mg/ml) for M4 = 4.72E-04; ESOL Solubility (mol/l) for M4 = 1.42E-06; ESOL Class value for M4 = MS; Ali Log S in M4 = -8.57; Ali Solubility (mg/ml) for M4 = 8.87E-07; Ali Solubility (mol/l) for M4 = 2.67E-09; Ali Class value for M4 = PS; Silicos-IT LogSw in M4 = -4.83; Silicos-IT Solubility (mg/ml) for M4 = 4.92E-03; Silicos-IT Solubility (mol/l) for M4 = 1.48E-05; Silicos-IT class value for M4 = MS; GI absorption by M4 = Low; BBB permeant in M4 = No; Pgp substrate in M4 = No; CYP1A2 inhibitor - M4 = Yes; CYP2C19 inhibitor - M4 = No; CYP2C9 inhibitor - M4 = Yes; CYP2D6 inhibitor - M4 = No; CYP3A4 inhibitor - M4 = No; log Kp (cm/s) for M4 = -2.69; Lipinski’s Rule violations by M4 = 1; Ghose’s Rule violations by M4 = 1; Veber’s Rule violations by M4 = 1; Egan’s Rule violations by M4 = 1; Muegge’s Rule violations by M4 = 2; PAINS # alerts for M4 = 0; Brenk # alerts for M4 = 1; Leadlikeness violations by M4 = 2; SA Score in M4 = 3.41; Bioavailability Score in M4 = 0.85 (Fig.1d; Table 2-6).

ADMET informatics of Cyclohexanol, 5-methyl-2-(1-methylethyl)- (M5)

MW of M5 = 198.3; # Heavy atoms in M5 = 14; # aromatic Heavy atoms in M5 = 0; Fraction Csp3 in M5 = 0.92; # rotatable bonds in M5 = 3; # H-bond acceptors in M5 = 2; # H-bond donors in M5 = 0; Molar refractivity in M5 = 58.97; Topological polar surface area of M5 = 26.3; Log Po/w value for M5 = 2.68; The octanol–water partition coefficient (XLOGP3) for M5 = 4; lipophilicity of large molecules (WLOGP) for M5 = 3.01; Moriguchi octanol-water partition coefficient (MLOGP) for M5 = 2.76; Silicos-IT Log P in M5 = 2.49; Consensus Log P in M5 = 2.99; ESOL Log S in M5 = -3.39; ESOL Solubility (mg/ml) for M5 = 8.05E-02; ESOL Solubility (mol/l) for M5 = 4.06E-04; ESOL Class value for M5 = S; Ali Log S in M5 = -4.25; Ali Solubility (mg/ml) for M5 = 1.10E-02; Ali Solubility (mol/l) for M5 = 5.57E-05; Ali Class value for M5 = MS; Silicos-IT LogSw in M5 = -2.15; Silicos-IT Solubility (mg/ml) for M5 = 1.41E+00; Silicos-IT Solubility (mol/l) for M5 = 7.13E-03; Silicos-IT class value for M5 = S; GI absorption by M5 = High; BBB permeant in M5 = Yes; Pgp substrate in M5 = No; CYP1A2 inhibitor - M5 = No; CYP2C19 inhibitor - M5 = No; CYP2C9 inhibitor - M5 = Yes; CYP2D6 inhibitor - M5 = No; CYP3A4 inhibitor - M5 = No; log Kp (cm/s) for M5 = -4.67; Lipinski’s Rule violations by M5 = 0; Ghose’s Rule violations by M5 = 0; Veber’s Rule violations by M5 = 0; Egan’s Rule violations by M5 = 0; Muegge’s Rule violations by M5 = 1; PAINS # alerts for M5 = 0; Brenk # alerts for M5 = 0; Leadlikeness violations by M5 = 2; SA Score in M5 = 2.92; Bioavailability Score in M5 = 0.55 (Fig.1e; Table 2-6).

ADMET informatics of 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (M6)

MW of M6 = 296.53; # Heavy atoms in M6 = 21; # aromatic Heavy atoms in M6 = 0; Fraction Csp3 in M6 = 0.9; # rotatable bonds in M6 = 13; # H-bond acceptors in M6 = 1; # H-bond donors in M6 = 1; Molar refractivity in M6 = 98.94; Topological polar surface area of M6 = 20.23; Log Po/w value for M6 = 4.66; The octanol–water partition coefficient (XLOGP3) for M6 = 8.19; lipophilicity of large molecules (WLOGP) for M6 = 6.36; Moriguchi octanol-water partition coefficient (MLOGP) for M6 = 5.25; Silicos-IT Log P in M6 = 6.57; Consensus Log P in M6 = 6.21; ESOL Log S in M6 = -5.98; ESOL Solubility (mg/ml) for M6 = 3.10E-04; ESOL Solubility (mol/l) for M6 = 1.05E-06; ESOL Class value for M6 = MS; Ali Log S in M6 = -8.47; Ali Solubility (mg/ml) for M6 = 9.94E-07; Ali Solubility (mol/l) for M6 = 3.35E-09; Ali Class value for M6 = PS; Silicos-IT LogSw in M6 = -5.51; Silicos-IT Solubility (mg/ml) for M6 = 9.06E-04; Silicos-IT Solubility (mol/l) for M6 = 3.05E-06; Silicos-IT class value for M6 = MS; GI absorption by M6 = Low; BBB permeant in M6 = No; Pgp substrate in M6 = Yes; CYP1A2 inhibitor - M6 = No; CYP2C19 inhibitor - M6 = No; CYP2C9 inhibitor - M6 = Yes; CYP2D6 inhibitor - M6 = No; CYP3A4 inhibitor - M6 = No; log Kp (cm/s) for M6 = -2.29; Lipinski’s Rule violations by M6 = 1; Ghose’s Rule violations by M6 = 1; Veber’s Rule violations by M6 = 1; Egan’s Rule violations by M6 = 1; Muegge’s Rule violations by M6 = 2; PAINS # alerts for M6 = 0; Brenk # alerts for M6 = 1; Leadlikeness violations by M6 = 2; SA Score in M6 = 4.3; Bioavailability Score in M6 = 0.55 (Fig.1f; Table 2-6).

ADMET informatics of Palmitic acid vinyl ester (M7)

MW of M7 = 282.46; # Heavy atoms in M7 = 20; # aromatic Heavy atoms in M7 = 0; Fraction Csp3 in M7 = 0.83; # rotatable bonds in M7 = 16; # H-bond acceptors in M7 = 2; # H-bond donors in M7 = 0; Molar refractivity in M7 = 89.45; Topological polar surface area of M7 = 26.3; Log Po/w value for M7 = 4.8; The octanol–water partition coefficient (XLOGP3) for M7 = 7.87; lipophilicity of large molecules (WLOGP) for M7 = 6.15; Moriguchi octanol-water partition coefficient (MLOGP) for M7 = 4.57; Silicos-IT Log P in M7 = 6.27; Consensus Log P in M7 = 5.93; ESOL Log S in M7 = -5.49; ESOL Solubility (mg/ml) for M7 = 9.07E-04; ESOL Solubility (mol/l) for M7 = 3.21E-06; ESOL Class value for M7 = MS; Ali Log S in M7 = -8.27; Ali Solubility (mg/ml) for M7 = 1.52E-06; Ali Solubility (mol/l) for M7 = 5.37E-09; Ali Class value for M7 = PS; Silicos-IT LogSw in M7 = -6.07; Silicos-IT Solubility (mg/ml) for M7 = 2.43E-04; Silicos-IT Solubility (mol/l) for M7 = 8.59E-07; Silicos-IT class value for M7 = PS; GI absorption by M7 = High; BBB permeant in M7 = No; Pgp substrate in M7 = No; CYP1A2 inhibitor - M7 = Yes; CYP2C19 inhibitor - M7 = No; CYP2C9 inhibitor - M7 = Yes; CYP2D6 inhibitor - M7 = No; CYP3A4 inhibitor - M7 = No; log Kp (cm/s) for M7 = -2.44; Lipinski’s Rule violations by M7 = 1; Ghose’s Rule violations by M7 = 1; Veber’s Rule violations by M7 = 1; Egan’s Rule violations by M7 = 1; Muegge’s Rule violations by M7 = 2; PAINS # alerts for M7 = 0; Brenk # alerts for M7 = 1; Leadlikeness violations by M7 = 2; SA Score in M7 = 3.44; Bioavailability Score in M7 = 0.55 (Fig.1g; Table 2-6).

ADMET informatics of γ Tocopherol (M8)

MW of M8 = 416.68; # Heavy atoms in M8 = 30; # aromatic Heavy atoms in M8 = 6; Fraction Csp3 in M8 = 0.79; # rotatable bonds in M8 = 12; # H-bond acceptors in M8 = 2; # H-bond donors in M8 = 1; Molar refractivity in M8 = 134.31; Topological polar surface area of M8 = 29.46; Log Po/w value for M8 = 5.76; The octanol–water partition coefficient (XLOGP3) for M8 = 10.33; lipophilicity of large molecules (WLOGP) for M8 = 8.53; Moriguchi octanol-water partition coefficient (MLOGP) for M8 = 5.94; Silicos-IT Log P in M8 = 9.2; Consensus Log P in M8 = 7.95; ESOL Log S in M8 = -8.29; ESOL Solubility (mg/ml) for M8 = 2.15E-06; ESOL Solubility (mol/l) for M8 = 5.16E-09; ESOL Class value for M8 = PS; Ali Log S in M8 = -10.89; Ali Solubility (mg/ml) for M8 = 5.38E-09; Ali Solubility (mol/l) for M8 = 1.29E-11; Ali Class value for M8 = IS; Silicos-IT LogSw in M8 = -8.79; Silicos-IT Solubility (mg/ml) for M8 = 6.80E-07; Silicos-IT Solubility (mol/l) for M8 = 1.63E-09; Silicos-IT class value for M8 = PS; GI absorption by M8 = Low; BBB permeant in M8 = No; Pgp substrate in M8 = Yes; CYP1A2 inhibitor - M8 = No; CYP2C19 inhibitor - M8 = No; CYP2C9 inhibitor - M8 = No; CYP2D6 inhibitor - M8 = No; CYP3A4 inhibitor - M8 = No; log Kp (cm/s) for M8 = -1.51; Lipinski’s Rule violations by M8 = 1; Ghose’s Rule violations by M8 = 3; Veber’s Rule violations by M8 = 1; Egan’s Rule violations by M8 = 1; Muegge’s Rule violations by M8 = 1; PAINS # alerts for M8 = 0; Brenk # alerts for M8 = 0; Leadlikeness violations by M8 = 3; SA Score in M8 = 5; Bioavailability Score in M8 = 0.55 (Fig.1h; Table 2-6).

ADMET informatics of ADMET informatics of Vitamin E (M9)

MW of M9 = 430.71; # Heavy atoms in M9 = 31; # aromatic Heavy atoms in M9 = 6; Fraction Csp3 in M9 = 0.79; # rotatable bonds in M9 = 12; # H-bond acceptors in M9 = 2; # H-bond donors in M9 = 1; Molar refractivity in M9 = 139.27; Topological polar surface area of M9 = 29.46; Log Po/w value for M9 = 6.04; The octanol–water partition coefficient (XLOGP3) for M9 = 10.7; lipophilicity of large molecules (WLOGP) for M9 = 8.84; Moriguchi octanol-water partition coefficient (MLOGP) for M9 = 6.14; Silicos-IT Log P in M9 = 9.75; Consensus Log P in M9 = 8.29; ESOL Log S in M9 = -8.6; ESOL Solubility (mg/ml) for M9 = 1.08E-06; ESOL Solubility (mol/l) for M9 = 2.50E-09; ESOL Class value for M9 = PS; Ali Log S in M9 = -11.27; Ali Solubility (mg/ml) for M9 = 2.30E-09; Ali Solubility (mol/l) for M9 = 5.33E-12; Ali Class value for M9 = IS; Silicos-IT LogSw in M9 = -9.16; Silicos-IT Solubility (mg/ml) for M9 = 2.97E-07; Silicos-IT Solubility (mol/l) for M9 = 6.89E-10; Silicos-IT class value for M9 = PS; GI absorption by M9 = Low; BBB permeant in M9 = No; Pgp substrate in M9 = Yes; CYP1A2 inhibitor - M9 = No; CYP2C19 inhibitor - M9 = No; CYP2C9 inhibitor - M9 = No; CYP2D6 inhibitor - M9 = No; CYP3A4 inhibitor - M9 = No; log Kp (cm/s) for M9 = -1.33; Lipinski’s Rule violations by M9 = 1; Ghose’s Rule violations by M9 = 3; Veber’s Rule violations by M9 = 1; Egan’s Rule violations by M9 = 1; Muegge’s Rule violations by M9 = 1; PAINS # alerts for M9 = 0; Brenk # alerts for M9 = 0; Leadlikeness violations by M9 = 3; SA Score in M9 = 5.17; Bioavailability Score in M9 = 0.55 (Fig.1i; Table 2-6).

ADMET informatics of Cholesta-7,9(11)-dien-3-ol, 4,4-dim (M10)

MW of M10 = 412.69; # Heavy atoms in M10 = 30; # aromatic Heavy atoms in M10 = 0; Fraction Csp3 in M10 = 0.86; # rotatable bonds in M10 = 5; # H-bond acceptors in M10 = 1; # H-bond donors in M10 = 1; Molar refractivity in M10 = 132.49; Topological polar surface area of M10 = 20.23; Log Po/w value for M10 = 5.07; The octanol–water partition coefficient (XLOGP3) for M10 = 8.53; lipophilicity of large molecules (WLOGP) for M10 = 7.94; Moriguchi octanol-water partition coefficient (MLOGP) for M10 = 6.62; Silicos-IT Log P in M10 = 7.03; Consensus Log P in M10 = 7.04; ESOL Log S in M10 = -7.44; ESOL Solubility (mg/ml) for M10 = 1.49E-05; ESOL Solubility (mol/l) for M10 = 3.61E-08; ESOL Class value for M10 = PS; Ali Log S in M10 = -8.83; Ali Solubility (mg/ml) for M10 = 6.14E-07; Ali Solubility (mol/l) for M10 = 1.49E-09; Ali Class value for M10 = PS; Silicos-IT LogSw in M10 = -6.5; Silicos-IT Solubility (mg/ml) for M10 = 1.31E-04; Silicos-IT Solubility (mol/l) for M10 = 3.18E-07; Silicos-IT class value for M10 = PS; GI absorption by M10 = Low; BBB permeant in M10 = No; Pgp substrate in M10 = No; CYP1A2 inhibitor - M10 = No; CYP2C19 inhibitor - M10 = No; CYP2C9 inhibitor - M10 = No; CYP2D6 inhibitor - M10 = No; CYP3A4 inhibitor - M10 = No; log Kp (cm/s) for M10 = -2.76; Lipinski’s Rule violations by M10 = 1; Ghose’s Rule violations by M10 = 3; Veber’s Rule violations by M10 = 0; Egan’s Rule violations by M10 = 1; Muegge’s Rule violations by M10 = 2; PAINS # alerts for M10 = 0; Brenk # alerts for M10 = 0; Leadlikeness violations by M10 = 2; SA Score in M10 = 6.32; Bioavailability Score in M10 = 0.55 (Fig.1j; Table 2-6).

ADMET informatics of γ-Sitosterol (M11)

MW of M11 = 432.72; # Heavy atoms in M11 = 31; # aromatic Heavy atoms in M11 = 0; Fraction Csp3 in M11 = 0.93; # rotatable bonds in M11 = 6; # H-bond acceptors in M11 = 2; # H-bond donors in M11 = 2; Molar refractivity in M11 = 136.28; Topological polar surface area of M11 = 29.46; Log Po/w value for M11 = 5.03; The octanol–water partition coefficient (XLOGP3) for M11 = 8.86; lipophilicity of large molecules (WLOGP) for M11 = 7.96; Moriguchi octanol-water partition coefficient (MLOGP) for M11 = 5.8; Silicos-IT Log P in M11 = 7.04; Consensus Log P in M11 = 6.94; ESOL Log S in M11 = -7.71; ESOL Solubility (mg/ml) for M11 = 8.46E-06; ESOL Solubility (mol/l) for M11 = 1.96E-08; ESOL Class value for M11 = PS; Ali Log S in M11 = -9.36; Ali Solubility (mg/ml) for M11 = 1.87E-07; Ali Solubility (mol/l) for M11 = 4.33E-10; Ali Class value for M11 = PS; Silicos-IT LogSw in M11 = -6.19; Silicos-IT Solubility (mg/ml) for M11 = 2.81E-04; Silicos-IT Solubility (mol/l) for M11 = 6.49E-07; Silicos-IT class value for M11 = PS; GI absorption by M11 = Low; BBB permeant in M11 = No; Pgp substrate in M11 = No; CYP1A2 inhibitor - M11 = No; CYP2C19 inhibitor - M11 = No; CYP2C9 inhibitor - M11 = No; CYP2D6 inhibitor - M11 = No; CYP3A4 inhibitor - M11 = No; log Kp (cm/s) for M11 = -2.65; Lipinski’s Rule violations by M11 = 1; Ghose’s Rule violations by M11 = 3; Veber’s Rule violations by M11 = 0; Egan’s Rule violations by M11 = 1; Muegge’s Rule violations by M11 = 1; PAINS # alerts for M11 = 0; Brenk # alerts for M11 = 1; Leadlikeness violations by M11 = 2; SA Score in M11 = 6.42; Bioavailability Score in M11 = 0.55 (Fig.1k; Table 2-6).

ADMET informatics of Stigmasta-5,24(28)-dien-3-ol, (3.β-24Z)- (M12)

MW of M12 = 412.69; # Heavy atoms in M12 = 30; # aromatic Heavy atoms in M12 = 0; Fraction Csp3 in M12 = 0.86; # rotatable bonds in M12 = 5; # H-bond acceptors in M12 = 1; # H-bond donors in M12 = 1; Molar refractivity in M12 = 132.75; Topological polar surface area of M12 = 20.23; Log Po/w value for M12 = 5.08; The octanol–water partition coefficient (XLOGP3) for M12 = 8.85; lipophilicity of large molecules (WLOGP) for M12 = 7.94; Moriguchi octanol-water partition coefficient (MLOGP) for M12 = 6.62; Silicos-IT Log P in M12 = 6.88; Consensus Log P in M12 = 7.08; ESOL Log S in M12 = -7.64; ESOL Solubility (mg/ml) for M12 = 9.36E-06; ESOL Solubility (mol/l) for M12 = 2.27E-08; ESOL Class value for M12 = PS; Ali Log S in M12 = -9.16; Ali Solubility (mg/ml) for M12 = 2.86E-07; Ali Solubility (mol/l) for M12 = 6.92E-10; Ali Class value for M12 = PS; Silicos-IT LogSw in M12 = -5.83; Silicos-IT Solubility (mg/ml) for M12 = 6.16E-04; Silicos-IT Solubility (mol/l) for M12 = 1.49E-06; Silicos-IT class value for M12 = MS; GI absorption by M12 = Low; BBB permeant in M12 = No; Pgp substrate in M12 = No; CYP1A2 inhibitor - M12 = No; CYP2C19 inhibitor - M12 = No; CYP2C9 inhibitor - M12 = No; CYP2D6 inhibitor - M12 = No; CYP3A4 inhibitor - M12 = No; log Kp (cm/s) for M12 = -2.53; Lipinski’s Rule violations by M12 = 1; Ghose’s Rule violations by M12 = 3; Veber’s Rule violations by M12 = 0; Egan’s Rule violations by M12 = 1; Muegge’s Rule violations by M12 = 2; PAINS # alerts for M12 = 0; Brenk # alerts for M12 = 1; Leadlikeness violations by M12 = 2; SA Score in M12 = 6.15; Bioavailability Score in M12 = 0.55 (Fig.1l; Table 2-6). BIOLED-Egg illustration of all the bioactive compounds in MONDRP is given in Fig. 2. Natural Product likeness density chart of bioactive compounds in MONDRP is given in Fig. 3 and the Swiss Target Prediction and Distribution Chart of all the selected bioactive compounds in MONDRP is given in Fig.  a-l.

Mutagenicity refers to the induction of permanent transmissible changes in the structure of the genetic material; Tumorigenicity refers to the process by which neoplastic cells are grown from tumors; Irritant refers to a stimulus from compound that causes irritation; Reproductive effective refers to adverse effect of compounds that interfere with the reproduction in an organism; logS value is estimated, and it is a unit-stripped logarithm (base 10) of the solubility measured in mol/liter. It is a value of the compound’s drug-like properties. The drug likeness is calculated by summing up score values of bioactive molecules in the present investigation. Drug score is composed of drug likeness, cLogP, logS, molecular weight and factors of toxicity risk management, and is used to judge the compound’s overall potential to qualify for a drug candidate. The value of the drug score is between 0 and 1, and the larger value means better pharmacokinetic properties (Table 7). 

CONCLUSION

                  Summative ADMET properties of all bioactive compounds Moringa oleifera Natural-Ripened-Dried (MONRD) Methanolic Pod Extract (MOMPE) as a potential source of natural drug lead namely - 7-Octadecyne, 2-methyl- (C₁₉H₃₆); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); 6,9,12,15-Docosatetraenoic acid, me (C₂₃H₃₈O₂); Cyclohexanol, 5-methyl-2-(1-methylethyl)- (C₁₀H₂₀O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C₂₀H₄₀O); Palmitic acid vinyl ester (C₁₈H₃₄O₂); .γ.-Tocopherol (C₂₈H₄₈O₂); Vitamin E (C₂₉H₅₀O₂); Cholesta-7,9(11)-dien-3-ol, 4,4-dim (C₂₉H₄₈O); γ.-Sitosterol (C₂₉H₅₀O); Stigmasta-5,24(28)-dien-3-ol, (3.β.,24Z)- (C₂₉H₄₈O) has been provided. All the compounds exhibited good gastrointestinal absorption with enhanced pharmacokinetic properties and low blood-brain barrier permeability. Further, work on the biomolecular and bioactivity aspects of these compounds in MONRD pod is expected to provide holistic baseline information for successful exploitation of lead candidates in drug design, development program.

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Table 1 List of Bioactive Compounds in Moringa oleifera Natural-Ripened-Dried Methanolic Pod Extract (MOMPE) with 2D structure

Table 2 Predicted Pharmacokinetic Properties for Absorption of bioactive compounds in MOMPE

Table 3 Predicted Pharmacokinetic Properties for Distribution of bioactive compounds in MOMPE

Table 4 Predicted Pharmacokinetic Properties for Metabolism and Excretion of bioactive compounds in MOMPE

Table 5 Predicted Pharmacokinetic Properties for Toxicity of bioactive compounds in MOMPE

Table 6 Predicted Medicinal Chemistry of bioactive compounds in MOMPE

Table 7 Summative contribution of different parameters to drug score of bioactive compounds in MOMPE