INTRODUCTION:

D-dimer is a peptide fragment that can be found in the bloodstream following the dissolution of a blood clot.It serves as an indicator of the existence of blood clots. D-dimer production occurs through the enzymatic degradation of a blood clot by plasmin. Plasmin degrades the fibrin mesh that constitutes a blood clot, resulting in the liberation of D-dimer into the circulatory system.

Increased concentrations of D-dimer can suggest the existence of a current blood clot or the recent development of a blood clot¹.

The prevalence of increased D-dimer levels varies according to the specific population under investigation and the circumstances in which the study is conducted.One study found that 74.6% of COVID-19 patients had increased D-dimer levels (≥ 0.50mg/L)². According to another study, the occurrence of high D-dimer levels in patients with COVID-19 was shown to be as high as 46.4%³. It is crucial to acknowledge that these statistics pertain exclusively to individuals diagnosed with COVID-19 and may not accurately reflect the broader community. Increased D-dimer levels can be linked to a range of illnesses, such as venous thromboembolism (VTE), sepsis, and cancer⁴.

Elevated levels of d-dimer were formerly considered to be of negligible significance. Nevertheless, a study has elucidated that among individuals with ischemic stroke who underwent intravenous thrombolysis using tissue plasminogen activator (tPA), there was a notable elevation in D-dimer levels subsequent to treatment, owing to the drug's ability to disintegrate blood clots. Elevated levels of D-dimer following thrombolysis were found to be correlated with a heightened likelihood of experiencing symptomatic intracranial hemorrhage and unfavorable functional outcom⁵. In pathological states characterized by continuous activation of coagulation, such as disseminated intravascular coagulation (DIC) or sepsis, there is an observed increase in levels of both D-dimer and FXIIa. This suggests simultaneous activation of the clotting process (elevated FXIIa levels) and the destruction of clots (elevated D-dimer levels)⁶.

Anticoagulants are drugs that impede the coagulation of blood, whereas anti-thrombolysis refers to the prevention or suppression of clot disintegration.The correlation between anticoagulants and anti-thrombolysis lies in the fact that anticoagulants function to inhibit the creation of blood clots, while anti-thrombolysis seeks to impede the dissolution of already-formed clots.Direct oral anticoagulants (DOACs) are a type of anticoagulant medication that is being used more frequently to treat and prevent venous thromboembolism (VTE) and stroke in individuals with atrial fibrillatio⁷.

Certain anticoagulant medications, like warfarin, possess a number of drawbacks, including the need for frequent blood tests to check their efficacy and necessitating dose modifications. There exist various food and medicine combinations that have the potential to elevate the risk of bleeding. The action of the treatment exhibits a gradual and prolonged initiation and conclusion. The narrow therapeutic window of a medication is characterized by its susceptibility to increased bleeding risk with even little adjustments in dosage⁸. Regarding the adverse effects of antithrombotic medications, Bleeding is the most prevalent adverse event and has the potential to be life-threatening. The incidence of serious or deadly bleeding is elevated in geriatric patients and individuals with renal or liver dysfunction. In addition to the aforementioned side effects, there are also reported occurrences of skin rashes, nausea, and hair loss, as well as cutaneous necrosis and purple toe syndrome in patients treated with warfarin. Heparin has the potential to induce thrombocytopenia, characterized by a decrease in platelet counts⁹. The safety and convenience of anti-thrombotic medications such as warfarin can be limited due to many factors. These include the need for frequent monitoring, potential interactions with numerous drugs and food, the danger of severe and occasionally deadly bleeding, as well as other associated adverse effects. Prudent patient selection and diligent monitoring are necessary in order to manage the delicate equilibrium between potential dangers and benefits effectively¹⁰.

The quest for novel anti-thrombotic medications is imperative due to the limitations in effectiveness, safety, and patient contentment associated with warfarin and direct oral anticoagulants (DOACs)¹¹. Certain patients may encounter adverse reactions or difficulties, thereby necessitating the development of medications that possess improved safety profiles and reduced side effects¹². The significance of plant-based therapies is increasing in contemporary times due to certain limitations linked with the utilization of the current pharmaceutical field¹³.

Turmeric, scientifically known as Curcuma longa Linn. (C.longa), comprises many bioactive components that possess potential anti-thrombotic or anti-coagulant activities. Curcumin is the most renowned and well-researched chemical, known for its demonstrated anti-inflammatory, antioxidant, and anti-thrombotic properties. Curcumin has been documented to hinder the process of platelet aggregation and diminish the creation of blood clots by regulating the function of different coagulation components, including thrombin and fibrinogen. Moreover, curcumin can also influence the expression of tissue factor, a protein that has a vital function in starting the process of blood clotting¹⁴.

The research findings indicate that curcumin has the ability to prolong blood coagulation durations, as evidenced by the examination of prothrombin time, thrombin time, and activated partial thromboplastin time ¹⁵. Previous research has provided evidence indicating that curcumin and its derivative bisdemethoxycurcumin (BDMC) had the ability to extend the duration of activated partial thromboplastin time (aPTT) and prothrombin time (PT). Additionally, these compounds have been shown to inhibit the activities of thrombin and activated factor X (FXa)¹⁶. Thrombin is the protein responsible for the conversion of fibrinogen into fibrin, which forms blood clots¹⁷.

Protein-ligand interaction plays a major role in structural drug design¹⁸. Docking studies are conducted to validate the results against the activity of a disease¹⁹. Docking studies have been widely used in looking at the interaction between drugs and receptors, such as for anti-inflammatory diseases²⁰, antibacterial²¹, diabetes, parkinson²², anticancer²³, anti-HIV²⁴, and anti-malaria²⁵.

The primary objective of this study was to examine the inhibitory potential of various components derived from Curcuma longa on coagulation factors XIIa. The aforementioned factors were selected as prospective targets for the development of low molecular weight inhibitors. Moreover, this enzyme assumes a crucial role in the mechanisms of hemostasis and thrombosis, and it is widely recognized as one of the strong stimuli for platelet secretion and aggregation. The aforementioned rationale has led to its recognition as a desirable candidate for the development of inhibitors within the realm of thrombotic disorders. Dabigatran (DAB) is well acknowledged as a highly effective inhibitor of this factor²⁶. The suppression of factor XIIa was reported as a result of the anticoagulant action of rivaroxaban (RIV) ²⁷ and apixaban (API)²⁸. The existing body of research offers substantiation that the inhibition of XIIa in animal models led to the complete prevention of induced thrombosis or a notable decrease in its subsequent effects²⁹.

Therefore, in this novel approach to drug lead development, a drug will be synthesized by employing virtual screening of secondary metabolite compounds derived from the rhizome of Curcuma longa Linn. The focus will be on inhibiting upstream processes, specifically targeting FXIIa, using an in silico approach that includes predictions of absorption, distribution, metabolism, excretion, and toxicity.

MATERIALS AND METHODS:

Search for Candidate Compounds:

The search for candidate compounds was achieved through the KNApSAcK Family, which was accessed through www.knapsackfamily.com. Accesed 11 August 2023

Selection of Candidate Compounds:

The selection of candidate compounds was accomplished via SwissADME, which is accessed through www.swissadme.ch. This selection was carried out with the consideration of "Drug-likeness" as the basis for making these compounds into medicinal compounds. "Drug-likeness" is considered in Lipinski's theory with the fulfillment of the compound according to Lipinski's theory.

Molecular docking simulation:

The study employed the Autodock 4.2 program in combination with the Lamarckian Genetic Algorithm (LGA) to assess the binding affinity and inhibitory capacity of the compounds under investigation against the coagulation components XIIa³⁰. The parameters employed in the LGA approach were as follows: The experiment consisted of a total of 27,000 generations, with a maximum of 250,000 energy evaluations. The mutation and crossover rates were set at 0.02 and 0.8, respectively. The incorporation of Kollman partial charges and polar hydrogens into the protein-ligand complexes was performed using AutoDockTools. The researchers considered the flexibility of the A-3OH and A4-OH molecules while maintaining the protein as a stiff structure. The process of molecular docking investigations encompasses a series of consecutive stages, which include the identification and preparation of the protein, the creation of the ligand, and the formation of the grid. The molecular docking simulation utilized optimized and structurally characterized geometries of the examined molecules. The 3D X-ray crystallographic structure of coagulation factor XIIa (PDB code 6B77, accession date: 17.3.2023; cocrystallized inhibitor: [3-(1-amino- isoquinoline-6-yl)phenyl]boronic acid) – INH3)³¹ was obtained from the RCSB Protein Data Bank. The protein structures that have been chosen exhibit a resolution of less than 3.0 Å, hence enabling precise forecasting of binding sites and interactions involving proteins and ligands. The ligands present in the binding sites of the examined coagulation factors, along with the co-crystallized water molecules, were removed using Discovery Studio 4.0 prior to conducting a molecular docking analysis. The dimensions of the search space for coagulation factor XIIa are defined as 98.689 × 82.084 × 18.257. The grid box size is set to 48 × 48 × 48Å, with uniform grid spacing parameter values^32–34.

Profile of Physicochemical Properties and ADMET of Candidate Compounds:

Candidate compounds that already have RS values that are better than standard ligands and existing drugs will be analyzed for the profile of adsorption, distribution, metabolism, extraction, and toxicity (ADMET).

RESULT:

Search and Selection Candidate Compound Docking:

A total of ninety-one substances derived from secondary metabolites of C. longa Linn rhizomes were obtained from www.knapsackfamily.com. . The compounds obtained were curcuminoids, volatile oils, flavonoids, and alkaloids.After considering the criteria of "drug similarity" based on Lipinski's theory from www.swissadme.ch, sixty-five compounds were selected for further analysis

Ligan Selection:

Crystal structures of target proteins were collected from the Protein Data Bank (PDB) web server (https://www. rcsb.org/) (Accessed March 17, 2023). The specific protein found in thrombosis was FXIIa (6b77) (fig.1), using validation methods in existing studies. So, the root-mean-squared deviation (RMSD) value of 0.375 Å was obtained.

Figure 1.3D Protein XIIa (6b77)

Molecular docking and visualization:

Molecular docking was performed to evaluate the ΔGbind (free energy) and Ki (inhibition constant) of the secondary metabolites in C.longa against the target protein 6b77. Table 1 records the ΔGbind and Ki of these compounds against protein 6b77. This analysis used several reference compounds that commonly interact with the target protein. Based on molecular docking, it was observed that there were two compounds with higher ΔGbind values (Demethoxy and Bisdemethoxy) compared to the ΔGbind values of two antithrombosis drug compounds (Rivaroxaban and Warfarin).In addition, related to the results of Ki values, it can be seen that Demethoxy and Bisdemethoxy compounds have smaller values compared to the Ki values of two antithrombosis drug compounds (Rivaroxaban and Warfarin).

Table 1. Molecular docking result ontarget proteins 6b77.

Compound	∆G_bind	K_i
Demethoxycurcumin	-9.5	108,01 nM
Bisdemethoxycurcumin	-9.23	171,66 nM
alpha-Turmerone	-8.01	1,34 µM
ar-Turmerone	-7.77	2,03 µM
Curcumin	-7.53	3,00 µM
Rivaroxaban	-9.16	191,79 nM
Warfarin	-8,24	915,46 nM

Visualization of the molecular tethering results was carried out to observe the structure and interactions between the compounds. The observed interactions include the total number of interactions and the type of interaction. Figure 2 illustrates the 2D binding diagram and 3D conformation visualization of the best molecular docking result, which is the visualization of Warfarin, Rivaroxaban, Demethoxy, and Bisdemethoxy on target protein 6b77.

Profile of Physicochemical Properties, Adsorption, Distribution, Metabolism, Excretion, and Toxicity of Candidate Compounds:

After the ADMET analysis process using the pkCSM page, the results in Table 2 show that the values for Molecular Weight, Hydrogen Bond Acceptors, Hydrogen Bond Donors, Polar Surface Activity of Demethoxy and Bisdemethoxy compounds.

Table 3 shows the absorption and distribution values of both compounds, this meets the criteria for absorption and distribution requirements as a drug candidate.

Figure 2. 2D and 3D representation of interactions between a) Rivaroxaban, b) Warfarin, c) Bisdemethoxy, d) Desmethoxy and amino acid residues of coagulation factor XIIa with interatomic distance obtained after molecular docking. Different colors indicate different types of interactions (legend).

Table 3 shows the results of the chemical physics profile of metabolism, excretion and toxicity of the two compounds, namely demethoxy and bisdemethoxy. but when viewed both compounds have interactions with CYP3A4.

DISCUSSION:

The concept of drug-likeness is employed to qualitatively evaluate the potential bioavailability of oral drug candidates based on their physicochemical characteristics. Drug similarity development has several advantages, including expediency and cost-effectiveness ³⁵. The drug similarity in this study was determined using Lipinski's Rule 5 (Ro5), Veber's rule, and Ghose's rule, which were assessed using online pkCSM. According to the Rule of Five (Ro5), orally active compounds must adhere to certain criteria, including a molecular weight (MW) of less than or equal to 500 Da, a logarithm of the partition coefficient (log P) of less than or equal to 5, a number of hydrogen bond donors (nHBD) of less than or equal to 5, and a number of hydrogen bond acceptors (nHBA) of less than or equal to 10. The TPSA, as determined by Veber's rule, is equal to or less than 140 square angstroms, while the number of rotatable bonds (nRB) is equal to or less than 10. The MRvalue, as defined by Ghose's rule, ranges from 40 to 140 cm3mol-1. The provided text consists of a numerical range enclosed in square brackets^36,37.

The KNApSAcK Metabolite Activity Data Base establishes triplet associations among organisms' metabolites, their biological activity, and their target species. This database enhances the understanding of the connections and interactions between metabolites in organisms and the chemical impact of metabolites on human health. In addition to metabolite activities pertaining to chemical ecology, almost 50% of the biological activities documented in the Metabolite Activity DB are linked to medicine and human health. In the future, the Metabolite Activity DB can be used to develop new medications and discover valuable resources for pharmacologically or nutritionally beneficial chemicals³⁸.

A total of ninety-one chemicals were derived as secondary metabolites from the rhizome of Curcuma longa Linn. A total of sixty-five compounds were chosen based on their adherence to the "drug-likeness" criteria, and subsequent docking tests were conducted. Once the docking process is completed, the rank scores are organized and subsequently compared to the values of the standard ligand and current drugs.

The initial step of the molecular docking procedure involves the validation of the docking approach by re-docking the standard ligand retrieved from the FXIIa receptor (6b77). In this process, the test ligand is utilized, while the binding site refers to the cavity where the standard ligand is situated ³⁹. The objective of the molecular docking investigation was to assess the inhibitory efficacy of secondary metabolite compounds derived from Curcuma longa on the enzyme coagulation factor XIIa. The quantitative thermodynamic parameters obtained are shown in Table 1. In addition.

The docking results identified several compounds from C. longa that exhibit the most favorable conformation with the lowest energy. The bioactive chemical with the lowest free binding energy was DMC, with a value of -9.5 kcal/mol. It was followed by BDMC, which had a free binding energy of -9.23 kcal/mol, and alpha turmerone, which had a free binding energy of -8.01 kcal/mol. However, the critical energy value of rivaroxaban was lower than the two highest compounds, at -9.07 kcal/mol, when compared to the positive control. The presence of large negative free binding energy (∆G) values indicates that protein-ligand binding occurs spontaneously and stabilizes protein-ligand interactions. Furthermore, they exhibit exceptional efficacy as molecular docking prediction inhibitors. The binding score that had the least value was shown to be directly connected with the lowest inhibition constant (Ki) value.

Based on the analysis of the provided parameters, it can be inferred that both examined compounds exhibit significant inhibitory effects in comparison with proven coagulation factor inhibitors. The findings from the molecular docking analysis indicate that Demethoxycurcumin and Bisdemethoxycurcumin exhibited higher inhibitory efficacy against coagulation factor XIIa in comparison to INH3 and Rivaroxaban.

As previously mentioned, the efficacy of the compound's bonding is promising; nevertheless, its effectiveness would be compromised in the presence of inadequate ADME features and elevated toxicity levels. This study examines over 2000 drugs sourced from the World Drug Index (WDI) to elucidate the essential parameters for compounds with favorable absorption or permeability. The findings indicate that molecules with satisfactory absorption or permeability characteristics must meet specific criteria, including a molecular weight of 500 or less, a partition coefficient of 5 or less, a maximum of 5 hydrogen bond donors, and a maximum of 10 hydrogen bond acceptors ⁴⁰. The standard being referred to is the Rule of Five, as proposed by Lipinski's Theory. A total of 91 candidate compounds were subjected to testing, out of which 66 compounds were found to conform to the characteristics outlined in Lipinski's Rule of Five. Subsequently, a comprehensive docking study was conducted in order to identify prospective compounds that exhibit favorable characteristics in terms of absorption and permeability.

The utilization of Caco-2 monolayer cells is a common practice in assessing the absorption profile of orally administered drugs. These cells serve as an in vitro model for the human intestinal mucosa. A substance with a log Papp value greater than 0.90cm/s 24 is indicative of favorable drug permeability. In the present investigation, it was shown that the Papp values of both substances exceeded 0.90 cm/s. It is widely recognized in the scientific community that compounds with an intestine absorption value (in humans) below 30% pose significant challenges in terms of absorption. The present study revealed that the compounds had intestinal absorption values over 30% in humans, hence providing evidence in favor of the notion that these compounds possess a high degree of absorbability⁴¹.

Within the distribution profile, it is observed that the anticipated value of the volume of distribution (VDss) exhibits a positive correlation with drug concentration in tissue relative to plasma. According to the available report, medicine is considered to possess a high volume of distribution at steady state (VDss) if it exceeds 2.81 L/kg (0.45).In contrast, a low VDss is indicated if it falls below 0.71L/kg (-0.15). The compounds exhibited VDss values of 0.143 and 0.14, which fall within an acceptable range and are neither excessively high nor excessively low. The capacity of a chemical to traverse the blood-brain barrier (BBB) is correlated with a logBB value beyond 0.3, while a logBB value below -1 indicates inadequate dispersion of the drug within the brain^42,43. The compounds Desmethoxy and Bisdemethoxy have demonstrated limited blood-brain barrier permeability, resulting in a lack of impact on the central nervous system.

Cytochrome P450 plays a significant role in drug metabolism within the metabolic profile, particularly when a molecule has the potential to induce alterations in the metabolic profile of other pharmaceuticals that warrant careful consideration. The phenomenon of enzyme isoform inhibition results in elevated amounts of free medicines in the bloodstream, hence leading to the manifestation of toxic symptoms, which represents the most notable consequence²⁷. The potential substances investigated in this investigation did not exhibit inhibitory effects on the CYP2D6 enzyme isoform. Nevertheless, it was observed that the substance Bisdemethoxycurcumin exhibited inhibitory effects on the isoform CYP3A4 of the enzyme.

The excretory profile involves the measurement of total clearance, which is determined by various excretion processes performed by elimination organs, such as the liver and kidneys. There exists a direct relationship between the total clearance of a medication and its rate of elimination from the body, whereby an increase in total clearance leads to an accelerated drug removal process, while a decrease in total clearance results in a slower elimination rate ^44,45. The analysis revealed that the log total clearance values for Demethoxycurcumin and Bisdemethoxycurcumin were determined to be 0.041 and -0.306, respectively. An additional benefit of considering these two compounds as potential therapeutic candidates lies in their lack of toxic effects in relation to mutagenic and hepatic toxicities.

CONCLUSION:

The primary objective of this study was to acquire and assess molecular docking, projected drug similarity, and ADMET assessments in secondary metabolite compounds of Curcuma longa Linn. The binding energies, ADMET properties, and drug resemblance of the ligands were compared to those of the control drug and rivaroxaban. Consequently, it is plausible that Demethoxycurcumin and Bisdemethoxycurcumin have inhibitory properties against FXIIa, thereby offering prospective benefits in thrombotic treatment.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 01.12.2023 Revised on 16.05.2024

Accepted on 27.08.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):152-158.

DOI: 10.52711/0974-360X.2025.00023

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

C_ID	MW	LogP	Torsion	HBA	HBD	PSA, A²	Water Solubility
Bisdemethoxycurcumin	308.333	3.3527	6	4	2	133.575	-3.382
Demethoxycurcumin	338,359	3,3613	7	5	2	145,054	-4,615

C_ID	Absorption			Distribution
C_ID	Intestinal Absorption	Skin Permeability	Caco-2 Permeability	Distribution Volume	BBB Permeability
Bisdemethoxycurcumin	91.081	-2.803	0.957	0.14	-0.089
Demethoxycurcumin	93,811	-3,192	1,098	-0,548	-0,389

C_ID	Metabolism		Excretion	Toxicity
C_ID	CYP2D6 Inhibitor	CYP3A4 Inhibitor	Total Clearance	Ames Toxicity	Hepatotoxicity
Bisdemethoxycurcumin	No.	Yes	-0.008	No	No
Demethoxycurcumin	No.	Yes	0,041	No	No