Exploring the Potential of Plant Bioactive Compounds against Male Infertility: An In Silico and In Vivo Study
Abstract
:1. Introduction
2. Results
2.1. Interaction Analysis
2.2. Drug Scanning
2.3. Molecular Dynamics Simulation Study
2.4. In Vivo Evaluation
2.4.1. Liver Function and Lipid Profile
2.4.2. Reproductive Hormones
2.4.3. Histo-Architecture of Liver and Testicular Tissue
3. Discussion
4. Materials and Methods
4.1. Retrieval and Optimization of Phytochemicals
4.2. Retrieval and Preparation of Receptor Proteins
4.3. Molecular Docking Study
4.4. Druggability Analyses
4.5. Molecular Dynamics Simulation Study
4.6. In Vivo Evaluation
4.6.1. Grou** of Animals and Doses Plan
4.6.2. Biochemical Determination
4.6.3. Determination of Hormones
4.6.4. Histological Examination of Tissues
4.6.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sr. No. | PubChem ID | Phytochemical | Receptor | Docking Score (kcal/mol) | Interacting Residues |
---|---|---|---|---|---|
1 | 5281702 | Tricin | SHBG (6PYF) | −11.09 | Ser42, Phe56, Asp65, Phe67, Leu80, Asn82, Met107, Val127, Leu131, Lys134, Ile141, Leu171 |
2 | 5281672 | Myricetin | −10.72 | Asn61, Asp64, Asp65, Gly129, Lys134, Arg135 | |
3 | 5280343 | Quercetin | −9.70 | Asp64, Asp65, His83, Trp84, Ser133, Lys134, Arg135 | |
4 | 159287 | Malvidin | −9.65 | Thr60, Asp64, Asn82, His83, Trp84, Ser133, Lys134, Arg135 | |
5 | 5281691 | Rhamnetin | −8.07 | Asn61, Asp64, His83, Gly129, Ser133, Lys134, Arg135 | |
6 | 5281702 | Tricin | ADAM17 (2I47) | −13.15 | Leu348, Gly349, Leu401, Val402, His405, His415, Val434, Pro437, Ala439, Val440 |
7 | 44256621 | Callistephin | −10.68 | Leu348, Leu401, Val402, His405, Glu406, His409, Pro437, Ala439, Val440 | |
8 | 370 | Gallic acid | −9.21 | Glu398, Val402, His405, Val434, Ala439, Val440 | |
9 | 9823887 | Rosavin | −9.14 | Gly349, Met345, Leu348, Tyr390, Leu401, Val402, His405, Glu406, Ala439, Val440 | |
10 | 489941 | Moronic acid | −9.07 | Met345, Leu350, His405, His409, His415, Ile438, Ala439 | |
11 | 9823887 | Rosavin | DNase 1 | −9.46 | Arg111, His134, Pro137, Tyr175, Tyr211, Asp251, His252 |
12 | 5281702 | Tricin | −9.23 | Glu39, Tyr6, Arg111, His252 | |
13 | 5281417 | Esculin | −8.55 | His134, Asn170, Tyr175, Tyr211, Asp251 | |
14 | 5281294 | Okanin | −8.00 | Glu39, Arg41, His134, Asn170, Asp251, His252 | |
15 | 442428 | Naringin | −7.82 | Arg111, His134, Pro137, Asn170, Ser174, Tyr175, Asp251 |
Sr. | Ligands | Target | Molecular Weight (<500 Dalton) | HBD (≤5) | HBA (≤10) | LogP (≤5) | Molar Refractivity (40–130) | Violations |
---|---|---|---|---|---|---|---|---|
1 | Tricin | SHBG ADAM17 DNaseI | 330.29 | 3 | 7 | 2.15 | 86.97 | 0 |
2 | Myricetin | SHBG | 318.24 | 6 | 8 | 0.79 | 80.06 | 1 |
3 | Quercetin | 302.24 | 5 | 7 | 1.23 | 78.03 | 0 | |
4 | Malvidin | 331.30 | 4 | 7 | 0.92 | 87.13 | 0 | |
5 | Rhamnetin | 316.26 | 4 | 7 | 1.63 | 82.50 | 0 | |
6 | Isorhamnetin | 316.26 | 4 | 7 | 1.65 | 82.50 | 0 | |
7 | Callistephin | ADAM17 | 468.84 | 7 | 10 | −1.71 | 112.12 | 1 |
8 | Gallic acid | 170.12 | 4 | 5 | 0.21 | 40.47 | 0 | |
9 | Kaempferol | 286.24 | 4 | 6 | 1.58 | 76.01 | 0 | |
10 | Moronic acid | 454.7 | 1 | 3 | 6.03 | 135.69 | 2 | |
11 | Rosavin | ADAM17 DNaseI | 428.4 | 6 | 10 | −1.07 | 101.30 | 1 |
12 | Esculin | DNaseI | 340.28 | 5 | 9 | −0.62 | 78.65 | 0 |
13 | Robinetin | 302.24 | 5 | 7 | 1.12 | 78.03 | 0 | |
14 | Okanin | 288.25 | 5 | 6 | 1.69 | 76.36 | 0 | |
15 | Naringin | 580.53 | 8 | 14 | −0.87 | 134.91 | 4 |
Category | Property | Myricetin | Malvidin | Rhamnetin | Quercetin | Isorhamnetin | Okanin | Callistephin |
---|---|---|---|---|---|---|---|---|
Absorption | Caco-2 > −5.15 | −5.653 | −5.159 | −5.109 | −5.204 | −5.056 | −5.375 | −6.196 |
Pgp-Substrate | −−− | ++ | −−− | −−− | −−− | −−− | + | |
Pgp-Inhibitor | −−− | −−− | −−− | −−− | −−− | −−− | −−− | |
HIA | −−− | −−− | −−− | −−− | −−− | −−− | ++ | |
Distribution | BBB | −−− | −−− | −−− | −−− | −−− | −−− | −− |
PPB | 92.77% | 93.13% | 96.30% | 95.45% | 96.24% | 99.08% | 89.62% | |
Metabolism | CYP1A2-Inhibitor | ++ | ++ | +++ | +++ | +++ | + | −−− |
CYP1A2 substrate | −− | ++ | + | −− | ++ | −−− | −−− | |
CYP2C19 inhibitor | −−− | −−− | −−− | −−− | −− | −−− | −−− | |
CYP2C19 substrate | −−− | −−− | −−− | −−− | −−− | −−− | −−− | |
CYP2C9 inhibitor | + | −−− | + | + | + | + | −−− | |
CYP2C9 substrate | − | ++ | ++ | + | ++ | − | − | |
CYP2D6 inhibitor | −−− | −−− | − | − | + | −−− | −−− | |
CYP2D6 substrate | −− | + | − | −− | − | −− | −− | |
CYP3A4 inhibitor | −− | −− | −− | − | + | −− | −−− | |
CYP3A4 substrate | −−− | −− | −−− | −− | −−− | −− | −−− | |
Excretion | Clearance | 7.716 | 11.093 | 8.284 | 6.991 | 16.361 | 7.971 | |
Toxicity | AMES | − | −− | + | + | + | ++ | ++ |
hERG | −− | −− | −−− | −−− | −−− | −−− | −−− | |
FDAMDD | + | +++ | − | −−− | −−− | − | −−− | |
H-HT | −−− | −−− | −−− | −−− | −−− | −− | −− | |
Category | Property | Kaempferol | Gallic Acid | Rosavin | Esculin | Robinetin | Tricin | |
Absorption | Caco-2 > −5.15 | −4.974 | −5.728 | −5.406 | −5.950 | −5.325 | −4.970 | |
Pgp-Substrate | −−− | −−− | − | − | −−− | +++ | ||
Pgp-Inhibitor | −−− | −−− | −−− | −−− | −−− | −−− | ||
HIA | −−− | −−− | +++ | ++ | −−− | −− | ||
Distribution | BBB | −−− | −−− | − | ++ | −−− | −−− | |
PPB | 97.86% | 53.49% | 43.91% | 56.10% | 94.64% | 91.48% | ||
Metabolism | CYP1A2-Inhibitor | +++ | −−− | −−− | −−− | ++ | +++ | |
CYP1A2 substrate | −− | −−− | −−− | −−− | −− | +++ | ||
CYP2C19 inhibitor | −− | −−− | −−− | −−− | −−− | −− | ||
CYP2C19 substrate | −−− | −−− | −−− | −−− | −−− | −−− | ||
CYP2C9 inhibitor | + | −− | −−− | −−− | + | + | ||
CYP2C9 substrate | ++ | −−− | −− | − | − | ++ | ||
CYP2D6 inhibitor | ++ | −−− | −−− | −−− | −− | + | ||
CYP2D6 substrate | −− | −− | −− | −− | −− | ++ | ||
CYP3A4 inhibitor | + | −−− | −−− | −−− | − | + | ||
CYP3A4 substrate | −−− | −−− | −−− | −−− | −−− | −− | ||
Excretion | Clearance | 6.868 | 10.108 | 1.218 | 4.015 | 7.773 | 6.626 | |
Toxicity | AMES | + | −−− | −− | −− | + | − | |
hERG | −−− | −−− | −−− | −−− | −−− | −− | ||
FDAMDD | −− | −−− | −−− | −−− | − | ++ | ||
H-HT | −−− | −− | −− | −− | −− | −−− |
Control | Intoxicated | Positive Control | Tricin (LD) | Tricin (HD) | |
---|---|---|---|---|---|
ALT (IU/L) | 46.2 ± 4.11 D | 113.8 ± 5.38 A | 68 ± 4.90 C | 89.5 ± 5.32 B | 35 ± 3.27 E |
AST (IU/L) | 51.8 ± 4.11 CD | 125.8 ± 6.55 A | 55.8 ± 3.30 C | 72 ± 5.72 B | 26 ± 3.27 E |
Urea (mg/dL) | 22 ± 1.63 C | 54 ± 4.90 A | 24 ± 2.45 B | 19 ± 0.82 D | 17 ± 0.82 DE |
Creatinine (mg/dL) | 0.8 ± 0.13 BC | 1.3 ± 0.08 A | 0.7 ± 0.16 BC | 0.7 ± 0.16 BC | 0.8 ± 0.13 BC |
Cholesterol (mg/dL) | 152 ± 5.72 DE | 198 ± 9.80 A | 160.8 ± 7.37 CD | 178 ± 8.16 B | 138 ± 4.90 F |
TG (mg/dL) | 173 ± 9.80 B | 221 ± 16.33 A | 122 ± 8.16 EF | 148 ± 7.35 CD | 137 ± 5.32 DE |
HDL (mg/dL) | 38 ± 1.63 CDE | 35 ± 2.45 F | 45 ± 2.45 A | 41 ± 2.45 ABCD | 42 ± 2.45 ABC |
LDL (mg/dL) | 80 ± 2.45 E | 87 ± 2.45 A | 85 ± 4.08 B | 84 ± 3.27 CD | 78 ± 2.53 F |
Control | Intoxicated | Positive Control | Tricin (LD) | Tricin (HD) | |
---|---|---|---|---|---|
TESTO (ng/mL) | 3.6 ± 0.02 A | 0.2 ± 0.01D | 2.1 ± 0.08 B | 1.8 ± 0.01 C | 2.1 ± 0.01 B |
LH (IU/L) | 0.8 ± 0.02 A | 0.2 ± 0.01 E | 0.6 ± 0.04 B | 0.4 ± 0.01 CD | 0.5 ± 0.02 C |
FSH (IU/L) | 0.8 ± 0.04 A | 0.3 ± 0.04 E | 0.7 ± 0.01 B | 0.3 ± 0.01 DE | 0.53 ± 0.02 C |
PROL (ng/mL) | 0.2 ± 0.04 C | 0.1 ± 0.01 D | 0.3 ± 0.02 B | 0.3 ± 0.02 B | 0.5 ± 0.02 A |
DHEA-SO4 (µg/dL) | 1.1 ± 0.10 E | 66.0 ± 3.27 A | 16.6 ± 0.82 B | 11.5 ± 0.82 C | 5.2 ± 0.01 D |
Group Number | Architecture Intact/Distorted | Necrosis | Periportal Inflammation Acute/Chronic | Congestion | Edema | Apoptosis | Hemorrhage |
---|---|---|---|---|---|---|---|
Control (G-1) | Intact | Not Seen | Not Seen | Not Seen | Not Seen | Not Seen | Not Seen |
Intoxicated (G-2) | Intact | Seen | Moderate, chronic++ | Not seen | Seen | Seen | Not seen |
Standard drug (G-3) | Intact | Not seen | Mild, chronic+ | Not seen | Seen | Seen | Not seen |
Test group (G-4) | Intact | Not seen | Mild, chronic+ | Not seen | Not seen | Seen | Not seen |
Group Name | Capsule | Seminiferous Tubules | Sertoli Cells | Germinal Cell Layer | Spermatogenesis | Tubular Necrosis | Edema | Inflammation |
---|---|---|---|---|---|---|---|---|
Control (G-1) | Intact | Intact | Seen | Seen | Seen | Not seen | Not seen | Not seen |
Intoxicated (G-2) | Intact | Altered | Seen | Cellular depletion | Not seen | Seen | Seen | Chronic++ |
Standard drug (G-3) | Intact | Intact | Seen | Cellular depletion | Diminished | Not seen | Not seen | Mild+ |
Test group (G-4) | Intact | Intact | Seen | Seen | Seen | Not seen | Not seen | Not seen |
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Jahangeer, M.; Mustafa, G.; Munir, N.; Ahmed, S.; Al-Anazi, K.M. Exploring the Potential of Plant Bioactive Compounds against Male Infertility: An In Silico and In Vivo Study. Molecules 2023, 28, 7693. https://doi.org/10.3390/molecules28237693
Jahangeer M, Mustafa G, Munir N, Ahmed S, Al-Anazi KM. Exploring the Potential of Plant Bioactive Compounds against Male Infertility: An In Silico and In Vivo Study. Molecules. 2023; 28(23):7693. https://doi.org/10.3390/molecules28237693
Chicago/Turabian StyleJahangeer, Muhammad, Ghulam Mustafa, Naveed Munir, Sibtain Ahmed, and Khalid Mashai Al-Anazi. 2023. "Exploring the Potential of Plant Bioactive Compounds against Male Infertility: An In Silico and In Vivo Study" Molecules 28, no. 23: 7693. https://doi.org/10.3390/molecules28237693