Computational Investigation of Isoquinoline Alkaloid from the Stems of Tinospora Cordifolia against Polycystic Ovarian Syndrome

doi:10.21203/rs.3.rs-1753057/v1

Polycystic Ovarian Syndrome (PCOS)is a global, substantial, metabolic, and endocrine health concern affecting one in every five women of progenitive aged (reproductive) women. Despite the fact that systematic screening and early diagnosis have improved the conception rate in recent decades, infertility still claims ~4%-20% of reproductive-aged women across the globe. In contemporary drug development, in-silico techniques are predominantly employed to investigate interactions between drugs and receptors, as well as quantum chemical properties. A computational approach was used in the current study to conform the quantum chemical properties, Density-functional theory (DFT) analysis, ADMET drug-likeness of the Isoquinoline, alkaloid [Berberine (BER), Palmatine (PAL), Jatrorrhizine (JAT), &Magnoflorine (MAG)], isolated from Tinospora cordifolia stem, and the four receptors were selected from PDB database.

Methods Docking studies were carried out withHuman Androgen Receptor(1E3G),Insulin receptor(3EKK), Estrogen Receptor beta(1U3S),and Human steroidogenic cytochromeP450 17A1(6WR0)by using AutoDockVina with a pliable ligand docking approach. ADMET prediction and toxicological predictions were performed using SwissADME. DFT analysis was used to predict the optimized structures and molecular electrostatic potential surfaces of the isolated compounds, GROMACS for Molecular Dynamic (MD) Simulation Studies.

Results and Discussion BER and PALshown better docking scores against the1E3Ghuman androgen receptor.The absorption of molecules through the skin was measured in cm/s by the skin permeability value (Kp). Higher negative values of MAG (-6.44), JAT (-5.9), PAL (-5.79), and BER (-5.78) resulted in lower skin permeation (log Kp, cm/s). CYP17A1 has a remarkable binding affinity for all four Isoquinoline alkaloids [BER (-5.46), JAT (-5.26), MAG (-6.13), and PAL (-6.01). Isoquinoline alkaloids (BER& PAL) have potential roles against various diseases, and in specific PCOS, scientific evaluation has been put forth based on virtual screening.

ADMET studies

DFT analysis

Docking studies

Isoquinoline alkaloids

Tinospora cordifolia

Hyperandrogenism, Insulin resistance, Estrogen dominance are the prime defining traits of women with PCOS. These traits lead to disruption of normal adrenal or ovarian functions resulting in impaired folliculogenesis [1] and eventually resulting in excess androgen production. The androgen receptor (AR) [2], Insulin receptor, Estrogen receptor [3] and CYP17A steroidogenesis receptors are linked to the PCOS phenotype and may also implicate in folliculogenesis, disruption of these receptors is responsible for the development of PCOS. Isoquinoline alkaloids are being employed to control androgen synthesis. Isoquinoline alkaloids [4] have a wide variety of medicinal value, therefore, of great interest. Berberine, magnoflorine, palmatine, jatrorrhizine, papaverine, morphine, codeine, corydaline, emetine and chelerythrine are among the most often used in traditional medicine. Tinospora cordifolia is one such a plant reported to be having rich in isoquinoline alkaloids like berberine, magnoflorine, palmatine, jatrorrhizine.

To understand the drug-receptor relationship and quantum chemical effects, in-silico studies are frequently employed in drug design with using AutoDockVina and a versatile ligand docking method to dock Human Androgen Receptor(1E3G),Insulin receptor(3EKK), Estrogen receptor beta(U3S),and Human steroidogenic cytochromeP450 17A1(6WR0). ADMET was performed by using the SwissADME prediction. DFT has become a strong tool in in-silico approach of chemistry because of its great potential. This approach was developed for spectroscopic investigation of chemical entities as a commanding utility. Frequency calculations and spectral intensity forecasts are now necessary for interpreting the experimental spectra of complex molecules [5]. Recent improvements in the in-silico approaches based on time dependent functional density theory (TDDFT) have resulted in increased interest in electronic structure calculations in exciting states [6]. The work sought to conduct a computational analysis, virtual docking simulation of isoquinoline (Proto-Berberine) compounds of Tinospora cordifolia, and the creation of novel suggested compounds against (PCOS) Androgen Receptor.

2.1 Virtual screening and docking

For all the compounds' 2D structures (.mol), ChemDraw 16.0 were used to examine the drawings (Fig. 1).Chem3D 16.0 which is used to convert all of the compounds (Berberine (BER) [7], Jatrorrhizine (JAT) [8], Magnoflorine (MAG) [9], and Palmatine (PAL) [10]) into a 3D structure (.pdb). Chem3D was utilised to load the 3D coordinates of each compound (.pdb) for energy simplification. For macromolecule preparation, the docking receptor (PDB codes 1E3G, 6WR0, 1U3S, and 3EKK) is a protein target from the RCSB Protein Data Bank.All bound ligands and water molecules were removed from the receptor's active site. The compounds (BER, JAT, MAG, and PAL)were docked against the active site of the protein using molecular docking assessment (AutoDockVina). Post-docking assessments were performed using AutoDock Tools [11].

2.2Computational Quantum Studies

Gaussian 09 was used to perform density functional theory (DFT) assessments on compounds (BER, JAT, MAG, and PAL), which was visualised using Gauss view 5.0. The structural variables of the lead compounds were improved by employing the B3LYP/6–31 G (d,p) basic level set with no symmetric constraints.The enhanced geometry yielded the molecular electrostatic potential map and the compounds' energies. The HOMO-LUMO energy gap, dipole moment, global softness, and electronegativity were all estimated using Koopman's approximation [12].

2.3 ADMET prediction

As computer mechanics advanced, in-silico methods such as network analysis and screening were widely used to illuminate the pharmacological underpinnings of traditional medicinal plant activities. Network pharmacology, in-silico screening, and pharmacokinetic screening can be used to supplement active molecules in these approaches. The Swiss Institute of Bioinformatics' (http://www.sib.swiss) ADME software (www.swissadme.ch) was used to estimate individual ADME behaviours of compounds using a web server that displayed the Swiss ADME Submission page. The list is constructed using the simplified molecular input line-entry system describes one source molecule per line with multiple inputs (SMILES) [13].

2.4 Molecular Dynamic (MD) Simulation Studies

For the MD simulation studies, the GROMOS 54A7 force field was employed. To convert pdb to gro format, which is accessed through GROMACS, the pdb2gmx utility was utilised. The PRODRG server was used to determine the ligands architecture and characteristics. After the 100ns simulation was finished, the data was evaluated using the GROMACS simulation programme. The root means square deviation (RMSD)(Backbone), root mean square fluctuation (RMSF)(c-alpha), radius of gyration (RG), and Molecular Mechanics Poisson Boltzmann Surface Area were all calculated using the gromacs package (MM PBSA).

Women with polycystic ovary syndrome (PCOS) have excessive androgen secretion, leading to ovulatory infertility and follicular maturation arrest, insulin resistance, and obesity. Recent research strongly suggests that insulin stimulates ovarian and adrenal steroidogenesis and pituitary LH release in PCOS patients by acting through its receptor. PCOS is a common endocrine disorder characterized by abnormal estrogen and estrogen receptor function in women [14–16].

Molecular docking was performed against the PCOS inhibitory receptor using AutoDockVina software. BER, JAT, MAG, and PAL were docked individually against with all the specified receptors such as androgen receptor [17], insulin receptor [18], estrogen receptor beta[19], and CYP17A1[20]. And the molecular docking results confirm the efficacy of BER and PAL with the H-bond interactions, and hydrophilic interactions with the proteins were better than JAT and MAG (Fig. 1). The better binding affinity was visualized in BER and PAL and acted as a potential inhibitor of PCOS (Fig. 2, 3, 4, & 5).CYP17A1 shows significant binding affinity with all the four compounds (BER (-5.46), JAT (-5.26), MAG (-6.13), and PAL (-6.01)) in the Tinospora cordifolia [21]. Binding affinity of berberine and magnoflorine with different receptors is mentioned in the Table 1& 2. Binding affinity of palmatine and jatrorrhizine with different receptors is mentioned in the Tables 3 & 4.

BER showed best docking results with Androgen receptor, and the ligand interactions to the androgen receptor in the amino acids such as Leu 301, Phe 356, Val338, Leu 339, Gly 342, Trp 312, Glu 305, Met 309, and Pro 227.The docking score showed the binding affinity value of BER was − 8.23 Kcal/mol.

Table 1

Comparative binding affinity of BER with different receptor
S.No	Receptors	Ligands	Binding Affinity (kcal/mol)
1.	Androgen receptor	BER	− 8.23
2.	Insulin receptor	BER	− 3.9
3.	Estrogen receptor beta	BER	24.9
4.	CYP17A1	BER	-5.46

MAG showed best docking results with insulin receptor among the four receptors, and the ligand interaction to the insulin receptors in the amino acid consists of Asp 1083, Ala 1028, Val 1010, Met 1076, Met 1139, Val 1060, Gly 1005, Lys 1030, and Ser 1006. The docking score showed the affinity value of MAG was − 6.31.

Table 2

Comparative binding affinity of MAG with different receptor
S.No	Receptors	Ligands	Binding Affinity (kcal/mol)
1.	Androgen receptor	MAG	1280
2.	Insulin receptor	MAG	-6.31
3.	Estrogen receptor beta	MAG	6.82
4.	CYP17A1	MAG	-5.26

PAL showed best docking results with Androgen receptor, and the ligand interaction to the androgen receptors in the amino acid consists of Leu 701, Leu 704, Leu 880, Gln 711, Met 745, Met 749, Met 780, Met 787, Phe 876, Phe 891, and Asn 705. The docking score showed the affinity value of PAL was − 6.71.

Table 3

Comparative binding affinity of PAL with different receptor
S.No	Receptors	Ligands	Binding Affinity (kcal/mol)
1.	Androgen receptor	PAL	-6.71
2.	Insulin receptor	PAL	-5.16
3.	Estrogen receptor beta	PAL	23.52
4.	CYP17A1	PAL	-6.13

JAT showed best docking results with CYP17A1 receptor, and the ligand interaction to the CYP17A1 receptors in the amino acid consists of Leu 452, Leu 370, Arg 440, Ser 441, Phe 435, Pro 434, Ile 371, Gys 442, Val 366, Val 310, and Ala 448. The docking score showed the affinity value of JAT was − 6.01.

Table 4

Comparative binding affinity of JAT with different receptor
S.No	Receptors	Ligands	Binding Affinity (kcal/mol)
1.	Androgen receptor	JAT	230
2.	Insulin receptor	JAT	150
3.	Estrogen receptor beta	JAT	33.8
4.	CYP17A1	JAT	-6.01

The results of 2-D and 3-D molecular docking visualization provide information that an interaction was formed between the BER, MAG, PAL and JAT, ligand against the various receptors of androgen receptor, insulin receptor, estrogen receptor, and CYP17A1.

BER and PAL showed better binding affinity to the PCOS androgen receptors than the other three receptors, whereas MAG & JAT Showed better binding affinity with insulin receptor and CYP17A1 receptor respectively. CYP17A1 had showed significant binding affinity with all the four compounds.

3.1 DFT Analysis of Isoquinoline alkaloids from stems of Tinospora cordifolia

BER, MAG, PAL, and JAT were first optimized using the B3LYP algorithm with a 6-31G (d) basis in Gaussian 16 utilizing Fukuis molecular orbital theory. The HOMO energy (EHOMO) and LUMO energy (ELUMO) of molecular orbitals were estimated. EHOMO and ELUMO are key characteristics that describe a molecule's ability to give and take electrons, respectively. In HOMO and LUMO, maps showing the density of electrons in different locations of the molecules were created and evaluated. The EHOMO and ELUMO values of BER, MAG, PAL, and JAT are shown in Table 5. The molecular orbitals; density maps were created and examined. The energy gap is proportional to the reactivity of a molecule, which can be linked to the change of molecules from HOMO to LUMO. As a result, the band energy gaps of BER, MAG, PAL and JAT have been estimated and displayed (Fig. 17).

The ability of the maps to donate or accept the electrons was calculated using the density functional theory. BER and PAL showed the lowest energy gap between HOMO and LUMO with the value of 0.158 eV and 0.161 eV. The chemical reactivity of a molecule can be linked to its molecular dipole moment since the two are proportionate. The molecular dipole moments of BER, JAT, and PAL were all greater than 2.0 debye, except MAG having the lowest at 0.95debye. We calculated the values of various descriptors such as Electronegativity (µ), Electrophilicity index (χ), Global softness (σ), and Absolute hardness (n) of the compounds using the EHOMO and ELUMO values. The electronegativity of a substance influences the ability of a molecule to receive electrons. A molecule's electronegativity determines how effective it is at inhibiting other molecules. BER has the lowest electronegativity among the other compounds (-0.0789), and then PAL has the lowest electronegativity value (-0.0805). The docking analysis is associated with the values of BER, JAT, MAG and PAL using conceptual DFT. In terms of all the compounds, we found that BER was the best scoring molecule among the compounds with a high docking score. Koopman's approximation was used to predict the HOMO-LUMO energy gap and related reactive elements. (chemical potential, hardness, softness, electronegativity, electrophilicity).

Table 5

DFT descriptors for compounds
Compounds	Dipole Moment	E_HUMO (eV)	E_LUMO (eV)	Energy gap ΔE (eV)	Absolute hardness (n)	Σ	Μ	Χ
BER	3.44	-0.199	-0.0411	0.158	0.079	6.32	-0.0789	0.0394
JAT	5.54	-0.195	-0.032	0.163	0.081	6.13	-0.0815	0.0410
MAG	0.95	-0.188	-0.005	0.183	0.091	5.55	-0.0915	0.0460
PAL	5.91	-0.196	-0.035	0.161	0.080	6.21	-0.0805	0.5031

In the above Table 5, σ- Global softness, µ - Electronegitivity, χ- Electrophilicity.

The results show that the BER had the smallest energy gap compared to the other compounds, indicating a high level of chemical reactivity and intramolecular charge transfer from HOMO to LUMO groups.

3.2 ADME Predictions of Isoquinoline alkaloids from stems of Tinospora cordifolia

ADME Predictions of Compounds

Table 6

ADME Predictions of Ligand Calculated by SwissADME
S.No	Ligands	Mol.Wt. (g/mol)	Number of Rotatable bonds	Number of Hydrogen acceptors	Number of Hydrogen donars	TPSA (Å²)	LogP
1	BER	336.36 g/mol	2	4	0	40.80	-1.27
2	JAT	338.38 g/mol	3	4	1	51.80	-1.49
3	MAG	342.41 g/mol	2	4	2	58.92	-2.00
4	PAL	352.40 g/mol	4	4	0	40.80	-1.46

Table 7

ADME Predictions of Ligands Calculated by SwissADME
S.No	Ligands	Skin Permeation Value (log Kp) cm/s	GI Absorption	BBB Permeability	Inhibitor Interaction
S.No	Ligands	Skin Permeation Value (log Kp) cm/s	GI Absorption	BBB Permeability	P-gp Substrate	CYP1A2 Inhibitor	CYP2C19 Inhibitor	CYP2C9 Inhibitor	CYP2D6 Inhibitor	CYP3A4 Inhibitor
1.	BER	-5.78	High	Yes	Yes	Yes	No	No	Yes	Yes
2.	JAT	-5.9	High	Yes	Yes	Yes	No	No	Yes	Yes
3.	MAG	-6.44	High	Yes	Yes	Yes	No	No	No	Yes
4.	PAL	-5.79	High	Yes	Yes	No	No	No	Yes	Yes

Computer-aided drug design has been used in the prediction of ADMET characteristics of medicines, resulting in early-stage drug development. Lipinskis rule [22] of five states that the drugs i.e. compounds, molecules and/or candidates must stick to the four parameter rule, according to this rule HBDs (hydrogen bond donors) must be less than five, HBAs (hydrogen-bond acceptors) must be less than ten, the value of log P cannot be less than 5,molecular mass must be less than 500 Da but according to Veber’s rule Topological polar surface area (TPSA) must not exceed 140. "Drug-likeness" refers to a prediction that an organic compound exhibits features that suggest it could be an orally active drug. The SwissADME predictions suggested that all of the compounds fulfilled Lipinski's rule of five, indicating that they are likely to be orally active in the current investigation. SwissADME was used to predict the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies of BER, MAG, PAL, and JAT.The absorption of molecules through the skin is measured in cm/s by the skin permeability value (Kp).Lower skin permeation (log Kp, cm/s) was obtained with a higher negative value as MAG (-6.44), JAT (-5.9), PAL (-5.79), and BER (-5.78).According to the SwissADME prediction variables, all of the compounds have enhanced gastrointestinal absorption, blood-brain barrier penetration, and are permeability glycoprotein substrates (P-gp).None of the substances are inhibitors of CYP2C19 or CYP2C9, according to the CYP interaction data. (Fig. 18).The PAL is also not an inhibitor of CYP1A2, while the other compounds are inhibitors of CYP1A2, CYP2D6, and CYP3A4. The method estimates bioavailability radar based on six physicochemical properties: polarity, lipophilicity, size, insolubility, flexibility, and insaturation, in order to discover drug-likeness.BER, MAG, PAL, and JAT are potential drug candidates from Tinospora cordifolia, according to bioavailability radar. These prognostic results should be verified in vitro and in vivo functional and pharmacological studies to treat PCOS.

The isolated compounds[23] optimized structures and molecular electrostatic potential surfaces were studied. The docking results in this study revealed that BER and PAL had higher docking scores against PCOS as an inhibitor. All four compounds (BER, JAT, MAG, and PAL) from stems of Tinospora cordifolia,according to SwissADME predictions, satisfies Lipinski's rule of five with zero violations.BER has a reduced electronegativity and global softness, implying that intramolecular charge transfer between electron-donor and electron-acceptor groups is significant, better bioactivity and chemical reactivity are predicted.This study reveals that BER and PAL from stems of Tinospora cordifolia may act as a lead molecule in inhibiting the formation of PCOS condition.

3.3 Molecular Dynamics (MD) Stimulatory studies

The complexes formed by docking two ligands were subjected to molecular dynamics (MD) simulation to better understand the conformational changes and stability of the ligand bound complexes, since it provides information on complex behaviour at the atomic level. GROMOS 54A7 force field was used for the simulation. The pdb2gmx tool was used to convert pdb to gro format, which is accessible via gromacs. The architecture and properties of the ligand were obtained using the prodrug server. Following that, a protein-ligand complex was created. The complex was solvated using the SPC water model and placed in the centre of a cubic periodic box. The system net charge was then neutralised by introducing counterions as needed. With the addition of 0.150 M of NaCl, the ionic strength was adjusted. The protein structure is then subjected to energy reduction using the steepest descent approach to eliminate unnecessary bonds, conflicts, and obtain a globally reduced state. After energy reduction, the system was equilibrated using two ensembles: Number of atoms, Volume of the system, and Temperature of the system (NVT) and Number of atoms, Pressure of the system, and Temperature of the system (NPT). The system was put through a production run once it reached equilibrium. The produced data was analyzed using the GROMACS simulation software once the 100ns simulation was completed. Using the gromacs package, we estimated root mean square deviation (RMSD)(Backbone), root mean square fluctuation (RMSF)(c-alpha), radius of gyration(RG), and Molecular Mechanics Poisson Boltzmann Surface Area(MM PBSA).

3.3.1 Molecular Dynamics (MD)

MD simulation was run on the Crystal Structure of the Human Androgen Receptor Complex with chosen ligands from docking PAL (Palmatine) and BER (Berberine). To understand the stability of the above-mentioned protein-ligand complexes, RMSD (Root Mean Square Deviation), RMSF (Root Mean Square Fluctuations), RG (Radius of Gyration), H-Bonds (Hydrogen bonds), and MMPSA calculations were carried out.

3.3.2 Root mean square deviation

It is a key criterion for determining the differences between the two confirmations. The greater the variance, the higher the RMSD value. For PAL, the RMSD values were determined to be steady from 30ns to 100ns, with a little fluctuation from 85ns to 90ns, and for BER, it was stable from 40ns to 100ns. In the RMSF plots, the amino acids implicated in bringing about the overall structural deviation are investigated. The RMSD results for PAL and BER are depicted in Figs. 7 & 8.

3.3.2 Root mean square fluctuation (RMSF)

RMSF study determines which amino acids in a protein cause more vibrations in the presence and absence of ligands, resulting in protein instability. A 0 to 100ns simulation timeframe is used to calculate the RMSF values.During the simulation, it was discovered that residues in the loop area fluctuate more. This means that during the 50ns simulation periods, the compound did not fluctuate.

3.3.3 Radius of Gyration (RG)

The radius of gyration may be used to evaluate the protein's compactness. The RG values versus a simulated timeline of 0 to 100000ps for PAL and BER were used to examine protein folding and unfolding.

3.3.4 Hydrogen Bond (H-bond)

The formation of hydrogen bonding stabilizes protein-ligand complexes. The hydrogen bonds produced in the molecular docking study are validated by simulation analysis in our research.

3.3.5 MMPBSA

MMPBSA determines how much energy is needed for ligands to bind to protein.

Table 8

MMPBSA of complicated PAL and BER of 100ns simulation
Target	Ligand code	Binding energy
	PAL	-211.219 +/- 9.358 kJ/mol
	BER	-93.681 +/- 11.349 kJ/mol

In this research to assess the potential Isoquinoline alkaloids against PCOS for drug interactions, drug-likeness, quantum chemical properties, and binding energy calculations, we used bioinformatics tools, including AutodockVina for molecular docking, Guaussian 09 for DFT analysis and SwissADME for admet analysis and GROMACS for molecular dynamic studies. BER and PAL have good binding affinity and better docking scores against the target receptor. CYP17A1 also shows significant binding affinity with all the four compounds (BER (-5.46), JAT (-5.26), MAG (-6.13), and PAL (-6.01)) in the Tinospora cordifolia. BER& PAL has superior bioactivity and chemical reactivity, according to DFT findings, since it has considerable intramolecular charge transfer between electron-donor and electron-acceptor groups. BER and PAL may serve as a lead molecule, and more research into functional group inclusion and modification is needed in order to generate novel compounds with therapeutic potential against PCOS disorders, according to the findings of this study.In addition to docking and DFT, the prediction of pharmacokinetics with special reference to ADME, bioavailability, and drug-like features of four compounds, BER and PAL, can be effective molecules for the novel drug candidate. However, further in vitro and in vivo assays for PCOS conditions are advised to confirm the prevailing predictions.

Acknowledgement

Sincer thanks to Dean Dr V Chitra for our support and motivation towards research

Authors contribution

Murali Krishna Moka (MKM): Methodology & experimentation; Writing and original draft preparation; Visulization;Sumithra M (SM): conceptualization; Investigation supervision; Writing-Revewing editing.

Disclosure statement

The Authors declare No conflict of Interest

Ashraf S, Nabi M, Rashid F, Amin S. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egyptian Journal of Medical Human Genetics. 2019 Dec;20(1):1-0.
Gao XY, Liu Y, Lv Y, Huang T, Lu G, Liu HB, Zhao SG. Role of Androgen Receptor for Reconsidering the “true” polycystic ovarian Morphology in pcoS. Scientific reports. 2020 Jun 2;10(1):1-7.
Jakimiuk AJ, Weitsman SR, Yen HW, Bogusiewicz M, Magoffin DA. Estrogen receptor α and β expression in theca and granulosa cells from women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2002 Dec 1;87(12):5532-8.
Khan AY, Suresh Kumar G. Natural isoquinoline alkaloids: binding aspects to functional proteins, serum albumins, hemoglobin, and lysozyme. Biophysical reviews. 2015 Dec;7(4):407-20.
Seminario JM. An introduction to density functional theory in chemistry. Theoretical and Computational Chemistry. 1995;2:1-27. DOI: 10.1016/S1380-7323(05)80031-7
Stratmann RE, Scuseria GE, Frisch MJ. An efficient implementation of time-dependent density-functional theory for the calculation of excitation energies of large molecules. The Journal of Chemical Physics. 1998;109:8218-8224. DOI: 10.1063/1.4774831
Mohan MC, Abhimannue AP. Identification and characterization of BER in tinosporacordifolia by liquid chromatography Quadrupole time of flight mass spectrometry (LC MS/MS q-tof) and evaluation of its anti inflammatory potential. Pharmacognosy Journal. 2017;9(3).
Sarma DN, Khosa RL, Sahai M. Isolation of JAT from Tinospora cordifolia roots. Plantamedica. 1995 Feb;61(01):98-9.
Ali H, Dixit S. Extraction optimization of Tinospora cordifolia and assessment of the anticancer activity of its alkaloid PAL. The Scientific World Journal. 2013 Jan 1;2013.
Patel MB, Mishra SM. MAG from Tinospora cordifolia stem inhibits α-glucosidase and is antiglycemic in rats. Journal of Functional Foods. 2012 Jan 1;4(1):79-86.
Karmakar B, Talukdar P, Talapatra SN. An in Silico Study for Two Anti-Inflammatory Flavonoids of Nerium Oleander on Proinflammatory Receptors. Res J Life Sci Bioinformatics, Pharm Chem Sci 2019;5(1), DOI: 10.26479/2019.0501.49.
Mumit MA, Pal TK, Alam MA, Islam MAAAA, Paul S, Sheikh MC. DFT Studies on Vibrational and Electronic Spectra, HOMO–LUMO, MEP, HOMA, NBO and Molecular Docking Analysis of Benzyl-3-N-(2,4,5-Trimethoxyphenylmethylene)Hydrazinecarbodithioate. J Mol Struct 2020;1220:128715, DOI: 10.1016/j.molstruc.2020.128715.
Daina A, Michielin O, Zoete V. SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci Rep 2017;7(October 2016):1–13, DOI: 10.1038/srep42717.
Diamanti-Kandarakis E, Dunaif A. Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications. Endocr Rev 2012;33(6):981–1030, DOI: 10.1210/er.2011-1034.
Gao X ying, Liu Y, Lv Y, Huang T, Lu G, Liu H bin, Zhao S gang. Role of Androgen Receptor for Reconsidering the “True” Polycystic Ovarian Morphology in PCOS. Sci Rep 2020;10(1):1–7, DOI: 10.1038/s41598-020-65890-5.
T. T, T. S, M. NN, H. Y, D. Y, M. O, N. M, T. K, Y. K, Y. N, H. F, M. NN, M. I, K. T, M. W, I. H, Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Nakagawa Y, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I, Arisawa T. Effect of MDR1 Gene Promoter Methylation in Patients with Ulcerative Colitis. Int J Mol Med 2009;23(4):521–527, DOI: 10.3892/ijmm.
Franks S, Hardy K. Androgen action in the ovary. Frontiers in endocrinology. 2018 Aug 10;9:452.
Poretsky L, Cataldo NA, Rosenwaks ZE, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocrine reviews. 1999 Aug 1;20(4):535-82.
Jansen HT, West C, Lehman MN, Padmanabhan V. Ovarian estrogen receptor-β (ERβ) regulation: I. Changes in ERβ messenger RNA expression prior to ovulation in the ewe. Biology of reproduction. 2001 Sep 1;65(3):866-72.
Kakuta H, Iguchi T, Sato T. The involvement of granulosa cells in the regulation by gonadotropins of Cyp17a1 in theca cells. in vivo. 2018 Nov 1;32(6):1387-401.
Chougale AD, Ghadyale VA, Panaskar SN, Arvindekar AU. Alpha glucosidase inhibition by stem extract of Tinospora cordifolia. Journal of Enzyme Inhibition and Medicinal Chemistry. 2009 Aug 1;24(4):998-1001.
Muralikumar V, Ramakrishnamacharya C, Seshachalam C. Inhibitory effect of phytochemicals from Azadirachtaindica a juss. and Tinospora cordifolia (thunb.) miers against SARS‐COV‐2 mpro and spike protease—An in silico analysis. International Journal of Engineering Applied Sciences and Technology. 2020;5(3):303-19.
Rajalakshmanan, Eswaramoorthy, Hailekiros H, Kedir F, Endale M. In Silico Molecular Docking, Dft Analysis and Admet Studies of Carbazole Alkaloid and Coumarins from Roots of Clausena Anisata: A Potent Inhibitor for Quorum Sensing. Adv Appl Bioinforma Chem 2021;14:13–24, DOI: 10.2147/AABC.S290912.

No competing interests reported.

Computational Investigation of Isoquinoline Alkaloid from the Stems of Tinospora Cordifolia against Polycystic Ovarian Syndrome

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials And Methods