A systematic computational DFT study for the phosphorus based drug-carrier mechanism for heparin a life-saving anticoagulant for cardiovascular diseases

doi:10.21203/rs.3.rs-4158936/v1

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A systematic computational DFT study for the phosphorus based drug-carrier mechanism for heparin a life-saving anticoagulant for cardiovascular diseases

https://doi.org/10.21203/rs.3.rs-4158936/v1

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Cardiovascular diseases (CVDs) are the major cause of global morbidity and mortality, representing a substantial burden on global healthcare. Thrombotic events serve as major determinants of patient outcomes. Heparin, an anticoagulant drug, is crucial in treating thrombotic disorders. Its clinical utility is limited due to the challenges related to targeted delivery. In this study, we employed computational material modeling techniques using DFT calculations to investigate the potential of black phosphorus as drug carrier for heparin drug delivery. Thermodynamic favorability of interaction between drug and carrier is investigated by adsorption energies calculations. Molecular orbital analysis reveals the electron transfer process and potential reactivity of drug, carrier and their complexes, important for understanding the drug delivery mechanism. The properties such as chemical potential, chemical hardness, chemical softness and global electrophilicity index are computed to study the stability of drug delivery complexes. Weak intermolecular interactions between heparin and black phosphorus are highlighted by non-covalent interaction (NCI) analysis. UV-vis analysis was employed to generate UV-vis spectra of drug delivery complexes. These spectra reveal the potential photochemical properties of complexes, crucial for triggering drug delivery mechanism. This study presents the valuable insights into the therapeutic potential of black phosphorus as drug carrier for heparin drug delivery to treat cardiovascular diseases such as thrombotic events.

Cardiovascular diseases (CVDs) represent a group of disorders that affect the heart and blood vessels. CVDs are a significant global health challenge and leading cause of mortality worldwide [1, 2]. There are various complications associated with cardiovascular diseases (CVDs) but thrombotic events are critical determinants of patient outcomes. Thrombotic events involve the formation of blood clots within the blood circulatory system. This abnormal blood clotting can cause serious complications which includes myocardial infarction (heart attack) and pulmonary embolism [3, 4, 5]. Therefore, the management and prevention of blood clot formation are the basic principle of cardiovascular medicines. Anticoagulant therapy is found to be effective in this regard, this prevents the formation of blood clots by inhibiting the coagulation cascade [6, 7].

Heparin, an anticoagulant drug performs a crucial role managing multiple thrombotic and cardiovascular diseases such as arterial thrombosis, pulmonary embolism and deep vein thrombosis because of its naturally occurring glycosaminoglycan. Besides, inhibition of key clotting factors such as factor Xa and thrombin particularly are its fundamental mechanisms of action. In this way is impedes the coagulation cascade and prevents the conversion of fibrinogen to fibrin, which is a critical step in formation of clot. Furthermore, heparin's rapid onset of action and short half-life make it an essential therapeutic agent for the prevention and treatment of acute thrombotic events, especially in high-risk clinical scenarios such as myocardial infarction, stroke, and post-surgical settings [8, 9, 10].

There are few challenges associated with the utility of heparin in clinical practices. These challenges include the need for parenteral administration, potential risk of bleeding complications, pharmacokinetics, and targeted delivery to the specific sites of action. Due to these limitations and challenges, there is a need for development of effective and innovative strategies for enhanced and targeted delivery of heparin [11, 14].

In this study, we aim to investigate the potential of black phosphorus as a drug carrier for heparin drug delivery. By employing computational material modelling techniques, specifically density functional theory (DFT) simulations, we aim to study the interactions between black phosphorus and heparin. Density functional theory (DFT) is a sophisticated quantum chemical method used to study the electronic structure of different materials. DFT is also helpful in determining the useful properties of the materials accurately. We carried out simulation by using GAMESS software, with 6-31g(d) B3LYP as basis set.

All calculations were performed using GAMESS [12] with DFT, an open an open source electronic structure code which facilitates in ab initio quantum chemical calculations. B3LYP functional and 6-31g(d) basis set were employed for geometry optimization of heparin, black phosphors, heparin black phosphorus complex HBP1, and HBP2. Different orientations of heparin on black phosphorus were investigated to identify the most stable geometry. Frequency calculations were used to validate the optimized structure as true minima by ensuring the absence of imaginary frequency [13, 14].

The structure modeling of heparin, black phosphorus and heparin-black phosphorus were carried out in Avogadro [15]. In our study, we calculated adsorption energies, HOMO (highest occupied molecular orbital) energies, LUMO (lowest unoccupied molecular orbital) energies, electron density and electrostatic potential distribution over the structure of complex [16, 17]. Furthermore, the parameters such as chemical potential (µ), chemical hardness (η), chemical softness (s), and electrophilicity index (ω) were computed at ground state optimized geometries of drug, black phosphorus and complexes to access their electronic properties [18].

Additionally, density of states (DOS) analysis was performed to study the electronic structure of drug, drug carrier and complexes. Non covalent interaction (NCI) analysis was employed to study the week molecular interactions between the heparin and black phosphorus using Multiwfn software package. In order to analyze the photochemical properties of drug and drug carrier complexes UV-vis absorption spectrum were generated by employing time dependent density functional theory (TD-DFT) calculations [19, 20, 21].

The optimized geometries of heparin and black phosphorus and heparin-black phosphorus complexes are shown in Fig. 1. It can be seen by the optimized geometries of drug and black phosphorus complexes that the drug molecule interacts with black phosphorus through P…H non covalent bonding interactions. In these complexes heparin molecule acts as hydrogen bond donor.

3.1 Study of geometry optimization process

Geometry optimization process of heparin, black phosphorus and HBP1, and HBP2 involves the convergence of energy and root mean square (RMS) values across optimization steps. This is shown in Fig. 2. In case of heparin, a gradual decrease in energy from − 906.6821 eV to -906.694 eV over 11 optimization steps can be seen, which indicates the approach towards a stable geometry. Similarly, the RMS values decreases from 0.0078 to 0.0006, indicating the reduction in atomic displacement and geometric convergence towards a minimum energy configuration

Likewise, black phosphorus molecule shows a consistent decrease in energy from − 2051.3478 eV to -2051.3621 eV and a decrease in RMS from 0.0117 to 0, indicating the convergence towards a stable geometry. Similarly, in case of drug and black phosphorus complexes HBP1 and HBP2 both demonstrates a consistent decrease in energy and RMS with respect to number of optimization steps. For HBP1 the energy decreases form − 2956.5729 eV to -2956.7742 eV, for HBP2, it decreases from − 2956.6611 eV to -2956.843 eV. The RMS value in both complexes decreases gradually along with optimization steps, which indicates the convergence of structure towards minimal atomic displacement and stable geometries.

3.2 Molecular orbitals (HOMO and LUMO) analysis

The HOMO, LUMO and HOMO-LUMO gap energies provide the critical information about the electronic properties of heparin, black phosphorus and their complexes HBP1 and HBP2. It is essential to understand these properties as they directly impact the interaction between drug and its carrier. These properties can influence the behavior of drug delivery system with biological systems. The values of E_HOMO, E_LUMO and E_g are presented in Table 01.

Table 1

Computed values of E_HOMO, E_LUMO and Eg for heparin, black phosphorus and their complexes HBP1 and HBP2
Name	E_total (eV)	E_HOMO (Hartree)	E_LUMO (Hartree)	E_g (Hartree)
Heparin	-906.6940	-0.16174	-0.6922	-0.5304
Black Phosphorus	-2051.3621	-0.19143	-0.12231	-0.0691
HBP1 Complex	-2956.7742	-0.25829	-0.12573	-0.1326
HBP2 Complex	-2956.8430	-0.25945	-0.13973	-0.1197

It can be seen that for heparin E_HOMO is -0.16174 Hartree and E_LUMO is -0.6922 resulting in an E_g of -0.5304. This small HOMO-LUMO energy gap indicates potential reactivity and electron transfer process. This is crucial for drug release mechanism. In case of black phosphorus, as drug carrier the value of HOMO-LUMO gap energy is -0.0691 Hartree, which is larger compared to the heparin drug. This indicates a more restricted electronic transition range and lower potential reactivity. The complexes HBP1 and HBP2 show intermediate E_HOMO, E_LUMO and, E_g values. These values suggest that the complexes have electronic characteristics from both the black phosphorus and heparin. This indicates potential synergistic effects in drug delivery applications. Figure 2 illustrates the HOMO and LUMO orbitals of heparin, black phosphorus and their complexes.

3.3 Electron density and electrostatic potential distribution

In Fig. 4, a uniformly distributed pattern of electron density and electrostatic potential along the structures of complexes HBP1 and HBP2 can be observed. This uniform distribution of electron density and electrostatic potential shows a balanced arrangement of electrons throughout the complexes structure. This even distribution is crucial for structural stability, coherence and functionality of drug carrier complexes. Furthermore, the balanced electrostatic potential can be observed across the both complexes. This indicates an equilibrium in distribution of electric charge within the complexes structure. This equilibrium is necessary for effective interactions between heparin (drug) and black phosphorus (drug carrier), which facilitates optimal drug encapsulation, smooth release and targeted drug delivery. This also helps in maintaining the structural stability of complexes in physiological environments.

3.4 Adsorption energies

The computed values of adsorption energies (E_ad) are shown in Table 2. The values of adsorption energies provide important insights into the interaction strength between drug and its carrier. In our case, the values of E_ad for HBP1 and HBP2 are − 1.2819 eV and − 1.2131 eV respectively. The negative values for adsorption energies for both complexes indicate thermodynamically favorable adsorption process. This shows that when drug interacts with drug carrier energy is released, making the process exothermic and spontaneous.

This kind of favorable interactions ensure that the heparin will remain securely bond to the black phosphorus. This minimizes the risk of premature release or degradation of drug during delivery or storage.

Table 2

Computed adsorption energies of complexes HBP1 and HBP2
Complex	E_ad (eV)
HBP1 Complex	-1.2819
HBP1 Complex	-1.2131

3.5 Chemical potential, chemical hardness, chemical softness and global electrophilicity index calculations

The chemical potential (µ), chemical hardness (η), chemical softness (s), and electrophilicity index (ω) for heparin, black phosphorus and their complexes HBP1 and HBP2 are provided in Table 3. It can be seen that the chemical chemical potential (µ) for complexes HBP1 and HBP2 are − 0.37086 hartree and − 0.37028 hartree respectively. These values are slightly higher than those for heparin and black phosphorus, which accounts for increased stability. Furthermore, the complexes show higher values of chemical hardness (η), and lower values of chemical softness (s) compared to drug and carrier, this indicates enhanced stability and reduced chemical reactivity. The lower values of electrophilicity index (ω) for complexes suggest reduced susceptibility to electron transfer and contributing to overall molecular stability of complexes. These parameters provide information about reactivity and stability of drug and carrier complexes, which are essential consideration in drug delivery application.

Table 3

Chemical potential (µ), chemical hardness (η), chemical softness (s), and electrophilicity index (ω) for heparin, black phosphorus and their complexes HBP1 and HBP2
Name	µ (Hartree)	η (Hartree)	s (Hartree ^− 1)	ω (Hartree)
Heparin	-0.41913	0.58087	1.721556	0.151213
Black Phosphorus	-0.40429	0.595715	1.678655	0.137185
HBP1 Complex	-0.37086	0.629145	1.589459	0.109302
HBP2 Complex	-0.37028	0.629725	1.587995	0.10886

3.6 Non covalent interaction (NCI) analysis

Non covalent interaction (NCI) analysis provides important insights into the weak interactions present in molecular structure. This analysis helps in distinguishing between strong directional attractions associated with localized atom-atom interaction and regions where weak interactions are present, as shown in Fig. 5.

In the case of complexes HBP1 and HBP2 formed between the drug heparin and carrier black phosphorus, the scattered graphs plotted between the reduced density gradient and electron density denoted by sign of λ₂ illustrate the presence of weak interaction forces between drug and its carrier. The green regions observed between black phosphorus and heparin indicates the van der Waals type weak intermolecular forces. Such weak interactions are useful as they facilitate the smooth and easy removal of heparin molecule from drug carrier at its targeted site of action.

3.7 Density of state (DOS) analysis

The density of state (DOS) analysis provides crucial information about the electronic structure and energy levels of materials. By observing the DOS plots, we can understand the distribution of electronic states and identify HOMO and LUMO orbitals. In this study, we used Multiwfn software to generate the DOS plots for heparin, black phosphorus and their complexes HBP1 and HBP2.

These DOS plots illustrates the distribution of electronic states relative to energy levels of the molecules. The dashed vertical line indicates the HOMO energy level on the plots. For heparin molecule the HOMO energy level is located at -0.16174 Hartree, while for black phosphorus it is at -0.19143 Hartree. Similarly, for HBP1 and HBP2 the HOMO energy levels are located at -0.25829 Hartree and − 0.25945 Hartree respectively. By analyzing these HOMO energy levels, we can get insights into the electronic properties and potential reactivity of the molecule.

3.8 UV- visible spectrum of drug delivery complexes

UV-Vis spectrum is necessary to investigate the photochemical, optical and electronic properties of a material. In our case we used time dependent DFT (TD-DFT) calculations to obtain the UV spectrum of drug delivery complexes HBP1 and HBP2. It can be seen that the both complexes have the values of wavelength in visible light region. Visible light region is between 300 to 700 nm. It means our drug carrier possess photochemical properties. This wavelength can be used to trigger the heparin release mechanism, when the light is absorbed by it. The UV-vis spectrums are shown in Fig. 7.

In this study we employed density functional theory (DFT) simulations to investigate the potential of black phosphorus as drug carrier for heparin drug delivery. Geometry optimization was performed to obtain the more stable geometries of drug, drug carrier and their corresponding complexes. Charge transfer from heparin to black phosphorus during the excitation from HOMO to LUMO was revealed by molecular orbital analysis. Balanced distribution of electron density and electrostatic potential, crucial for stability was observed along the structures of complexes formed between drug and drug carrier. The negative sign of calculated adsorption energies indicated that the adsorption of drug over drug carrier was spontaneous and thermodynamically favorable. The chemical potential (µ), chemical hardness (η), chemical softness (s), and electrophilicity index (ω) for heparin, black phosphorus and their complexes HBP1 and HBP2 provided the valuable information about the stability and potential reactivity. Weak intermolecular forces such as van der Waals interactions between heparin and black phosphorus were observed by NCI analysis. Distribution of electronic states and identification HOMO and LUMO orbitals within heparin, black phosphorus and their complexes HBP1 and HBP2 were observed by density of states (DOS) analysis.

Author Contribution

All authors reviewed the manuscript and approved.

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No competing interests reported.

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A systematic computational DFT study for the phosphorus based drug-carrier mechanism for heparin a life-saving anticoagulant for cardiovascular diseases

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Abstract

Figures

1. Introduction

2. Computational details

3. Results and discussion

3.1 Study of geometry optimization process

3.2 Molecular orbitals (HOMO and LUMO) analysis

3.3 Electron density and electrostatic potential distribution

3.4 Adsorption energies

3.5 Chemical potential, chemical hardness, chemical softness and global electrophilicity index calculations

3.6 Non covalent interaction (NCI) analysis

3.7 Density of state (DOS) analysis

3.8 UV- visible spectrum of drug delivery complexes

Conclusion

Declarations

Author Contribution

References

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