Delivery of Mavacamten and Olutasidenib Drugs by ?-Cyclodextrin Through Supramolecular Host-Guest Inclusion Complex Formation: A Theoretical Study

The emergence of targeted drug delivery is to deliver most of the administered drug to the target, while eliminating or minimizing the accumulation of the drug at any non-target sites and with minimum side effects associated with the use of free drugs[1]. Nanocarriers offer several advantages over traditional drug therapies as it is easier to customize their size, charge, surface properties and targeting moieties to regulate their uptake, biodistribution, targeting and elimination[2,3]. Due to their tiny size, giant surface area and feasible targetability, nanocarriers have optimized efficacy, decreased side effects, enhanced drug bioavailability and improved stability[4,5]. Drugs can either be dispersed into the nanocarrier matrix or located within the nanocarrier layers[6].  There are different types of nanocarriers that have been synthesized for drug delivery including dendrimers, liposomes, solid lipid nanoparticles, polymersomes, polymer–drug conjugates, polymeric nanoparticles, peptide nanoparticles, micelles, nanoemulsions, nanospheres, nanocapsules, nanoshells, carbon nanotubes, silicon nanotubes and gold nanoparticles[7,8] [9].  Some widely recognized host moieties in this area include Crown ether, porphyrin[10] calixarenes [11], pillararenes, cyclodextrins [12-15], cucurbituril [16,17]and rotaxane. Cyclodextrins are cyclic oligosaccharides linked by α-1,4 bonds and derived from starch that has been broken down by glucosyltransferase[18,19] . The natural cyclodextrins α-, β-, and γ-CDs are composed of 6, 7, or 8 glucose units and their synthetic derivatives are divided into three groups: hydrophilic, such as 2-hydroxypropyl-β-CD (HP-β-CD); hydrophobic, such as 2,6-di-O-ethyl- β-CD; and ionizable, such as sulfobutylether β-CD (SBE-β-CD). The CDs have a truncated cone-resembled shape with a hollow cavity. The sizes of the primary and secondary sides of the CDs depend on the unit number of glucose. The depth of the hollow cavity is 0.78 nm for all three types of CDs. The hydroxyl groups of the glucose units are oriented toward the outside at the orifice of the two ends, while methinic protons are located inside the cavity, the structure of which enables CDs with hydrophilic external surface and hydrophobic hollow cavity[20]. Thus, a variety of guests can be encapsulated into the cavity via the host–guest interaction in aqueous conditions and even in the solid state, which include small molecules, cationic or anionic guests, proteins, and polymer chains. The free hydroxyls on the outside of the CDs impart a more hydrophilic character, whereas the oxygen atoms in the glycosidic bonds and the hydrogen atoms impart a hydrophobic character within the cavity, which allows the dissolution in aqueous medium of compounds with low solubility. Different drugs used in cancer[21], COVID[22-26], cardiac recovery[27] have huge side effects. Mavacamten is the first and only cardiac myosin inhibitor used for the treatment of adults with obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms[28]. Mavacamten sometimes cause harmful effects in people. Mavacamten reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Some other mild side effects have been reported with Mavacamten. These include dizziness, fainting, mild allergic reaction, liver problems, and kidney problems[29].  

Mavacamten is also acknowledged as an endocrine disrupting compound (EDC)[30]. Research has shown that Mavacamten exposure negatively impacts the functions of the brain, thyroid, ovaries, and reproductive organs, resulting in cardiovascular diseases, obesity, carcinogenic effects, neurotoxicity, and issues with child growth[31]. Consequently, regulatory agencies in numerous countries have confirmed that mavacamten is a toxic substance. Thus, to predict mavacamten's exposure and potential health effects, it must be monitored frequently in drinking water. Olutasidenib serves as a beta-blocker medication. It is indicated for treating hypertension, hyperthyroidism, migraine[32,33] and certain cases of cardiac arrhythmia. Olutasidenib devastates steroid hormone levels, and causes different health related problems in humans[32]. Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation[34]. Olutasidenib causes several hazards to patient’s health like liver toxicity, electrolyte (Sodium, Potassium) abnormalities, kidney problems, nausea and/or vomiting, fatigue, muscle or joint pain/aches and headache, constipation, leukocytosis (increased White Blood Cell Count), shortness of breath (Dyspnea), rash, mouth ulcers (Mucositis), diarrhea, fever[33,35]. To mask their associated side effects and increase bioavailability we will make their respective inclusion complexes with supramolecular host β-Cyclodextrin (β-CD)[36]. Subsequently we will evaluate their stability by different theoretical parameters like adsorption energy, projected density of states[37], charge density, Mulliken charge analysis[38] and Molecular Dynamics Simulation[39].

In this work, we conducted a quantum chemistry investigation of β-CD and its inclusion complexation with two significant anti-cancer drugs, Mavacamten and Olutasidenib, aimed at minimizing their usage and side effects.

Computational details:

All density functional theory (DFT) calculations in our present work were carried out using the Gaussian 16 program [40]. Ground state geometry optimizations of the of β-Cyclodextrin, Mavacamten, Olutasidenib and the inclusion complexes in aqueous medium were performed at B3LYP/6-31+G(d) level of theory[41]. We have chosen dispersion corrected hybrid B3LYP-D-3 functional through the 6-31+G(d)  basis set which is pretty reliable and precisely defines the non-covalently bonded interaction energies (hydrogen bonding, π–π stacking) present in the π-system [42]. The optimized geometries correspond to minima on the potential energy surfaces were confirmed by vibration frequency analysis at the identical level of theory. Different types of weak interactions like H-bonding, van der Waals and steric interactions were envisaged by Non Covalent Interaction (NCI) [43] index plots of the reduced density gradient (RDG or s) vs. molecular density ρ were analyzed using the Multiwfn 2.6 suite[44] at the ground state geometries. Molecular electrostatic potential (MESP) maps were produced at the identical level of theory to know the range of existing charge transfer interactions in the inclusion complexes. Furthermore, adsorption energies or binding energy (ΔE_ads) for all inclusion complexes were evaluated by the following formula:

ΔE_ads = E_{inclusion-complex} - E_CD - E_{Mavacamten/Olutasidenib}

Where E_{inclusion-complex}, E_CD, E_{Mavacamten/Olutasidenib} are the total energy of the geometry optimized inclusion complex (i.e. Mavacamten-β-CD and Olutasidenib-β-CD, β-CD, Mavacamten/Olutasidenib) in aqueous medium respectively. In order to analyze the contributions from host and guest moieties in HOMO and LUMO of the composite systems, the projected density of states (PDOS) analysis have been carried out.

The interaction of Mavacamten-β-CD and Olutasidenib-β-CD complexes were simulated by employing the atom centered density matrix propagation (ADMP) approach at the identical level of theory with a step-size of 1000 over a timeframe of 45 femtosecond. We have analyzed the geometric parameters and energy fluctuations of these complexes for each 10 fs.

RESULTS AND DISCUSSIONS:

Stable structures and binding energy analysis:

Ground state optimized configurations of host-guest inclusion complexes of Mavacamten and Olutasidenib with β-CD are presented   in Figure 2. The negative binding energies listed in Table 1 confirm that both Mavacamten and Olutasidenib form stable complexes with β-CD, demonstrating a thermodynamically favorable inclusion process (Figure 2). The global and geometric parameters like HOMO, LUMO, chemical potential, bang gap, global hardness, global softness, electro-negativities and electrophilicity index in water medium are illustrated in Table 1. The strong hydrogen bonds (indicated by dashed lines in Figure 2) are crucial for holding Mavacamten (3.51 Å, 3.57 Å) and Olutasidenib (2.12 Å, 3.03 Å, 3.71 Å, 3.91 Å, 3.95 Å) tightly within the β-CD host. These bond lengths clearly demonstrate the significant strength of H-bonding in these supramolecular complexes, contributing to their enhanced stability. 

Table 1:  Adsorption Energy, HOMO, LUMO levels band gap and other global parameters for Mavacamten, Olutasidenib Mavacamten-β-CD and Olutasidenib-β-CD Composites in water medium

Computational frequency analyses facilitated the evaluation of thermodynamic parameters. The calculated thermodynamic parameters such as the enthalpy change (ΔH°), the thermal Gibbs free energy (ΔG°) and entropy contribution (ΔS°) calculated at PM7 are summarized in Table 2. The data presented in Table 2, specifically the negative ΔH° and ΔG° values, are found to be consistent with an exothermic and spontaneous complex formation at standard temperature and pressure (298.15 K, 1 atm). The ΔS° change for the inclusion complexes were found negative, indicating a decrease in disorder. We note that the negative entropy change (ΔS°) is the steric barrier caused by molecular geometrical shape and the limit of β-CD cavity to the freedom of movement and rotation of guest molecule. Thermodynamic analysis, revealing negative enthalpy and entropy changes, indicates that the inclusion complex formation is an enthalpy-driven and spontaneous process. The adsorption, solvation energy, and thermodynamic data collectively indicate that the composites present a viable mechanism for the attenuation of drug toxicity and the achievement of sustained drug release.                  Table 2:  ΔG° (kcal); ΔH° (kcal) and ΔS° (cal/K) for Mavacamten-β-CD and Olutasidenib-β-CD Composites in water medium (calculated at RPM7/ZDO level of theory).

Frontier molecular orbital and charge transfer characteristics:

Frontier molecular orbital (FMO) analysis has been performed to understand the stability of the inclusion complexes. The kinetic stability, chemical reactivity, and chemical hardness are often predicted from the energy gap between HOMO and LUMO. The global reactivity descriptors of molecules like chemical potential (μ), electronegativity (χ), softness (S), hardness (η) and electrophilicity index (ω) have been derived from HOMO and LUMO energy values [50, 51] and they were calculated from the equations using Koopman’s theorem for closed-shell molecules. The global reactivity descriptors in water phase are reported in Table 1. The negative chemical potential (μ) values confirm that the studied inclusion complexes are quite stable. Mavacamten's electronegativity (χ) is greater than that of its composite, while Olutasidenib and its composite exhibit the same electronegativity. The softness (S) value of the drug and its corresponding composite was identical in both experimental systems. The global hardness (η) of the Mavacamten composite increases upon its inclusion in the host cavity, a trend reversed for Olutasidenib. Conversely, the electrophilicity index (ω) shows an opposite trend to global hardness. The 3D plots of the HOMO and LUMO orbitals computed at the B3LYP/6-31+G(d) level for all the complexes are shown in Figure 3. A careful scrutiny of FMO plots of encapsulated composites revealed that only guest molecule Mavacamten and Olutasidenib contribute to both HOMO and LUMO level. Such spatial distribution of HOMO-LUMO charge densities evidently demonstrates that charge transfer involving host-guest interaction is absent in these complexes.

To gain a quantitative insight on the charge transfer from host to guest, the Mulliken charge analysis was done. It is found that in Mavacamten-β-CD inclusion complexes, Host moiety acts as an acceptor and the guest acts a donor, whereas, in Olutasidenib-β-CD, Host moiety acts as donor and the guest acts an acceptor. The substantial charge transfer from host to guest is shown in figure 4.

The electrostatic potential maps (ESP) is a vital tool to understand the molecular interactions in a given molecule. It is very useful for interpreting and predicting relative reactivity sites for electrophilic and nucleophilic attack and hydrogen bonding interactions. The ESP for all the complexes is plotted in the figure 5. The red coloured region signifies the area of negative electrostatic potential. As seen in figure 5, the  red region is more prominent in case of Olutasidenib-β-CD. We have also plotted projected density of states as illustrated in the figure 6 which also suggests donor acceptor interactions and contributions of theses moieties to the conduction and valence bands of the composite systems.

Study of ADMP Dynamics of the inclusion complexes:

To account the stability of the micro system molecular dynamics and trajectory analysis of these inclusion complexes were performed. We have chosen ADMP method as it is a reliable approach to examine the molecular stability and dynamics of macrosystems. The dynamic stabilities of the optimized geometries of Mavacamten-β-CD and Olutasidenib-β-CD inclusion complexes were simulated by employing the ADMP method in vacuum (as implemented in Gaussian 16 programme package). The plots of simulated total energies and time are shown in figure 7.

As shown in figure 8 ( a & b), the typical snapshots at each 10fs are collected. It is noteworthy to notice that during the ADMP simulations, Mavacamten and Olutasidenib moiety is tightly bound within the CD cavity owing to the formation of strong H- bonding. Strong H bonding and  low level of fluctuations are indicative of high stability of inclusion complexes.

Figure 8 (a)  ADMP snapshots for Mavacamten-β-CD inclusion complexes at 10 fs

Non Covalent Interactions?Reduced Density Gradient analysis:

To analyze non-covalent interactions like van der Waals, H-bonding, steric interactions, non-covalent index (NCI) technique have been used. The plots of reduced density gradient (RDG) against electron density multiplied by the sign of the second Hessian eigenvalue (sign(λ2)ρ)  for these supramolecular complexes are shown in figure 9. It is well known that reduced density gradient, appeared to be a practically helpful quantity [46] for the description of non-covalent interactions. In order to differentiate between stabilizing and destabilizing interactions, the eigenvalues (λi ) of the second derivative of density is plotted within the framework of NCI technique and one can easily illustrate information about non-covalent interactions from the plots of sign(λ2)ρ  vs. s. The stabilizing interactions are indicated by negative values while the repulsive interactions are characterized by positive values of sign(λ2)ρ . Red, blue and green colors in graphs are signifying the attractive H-bonding, van der Waals, and repulsive steric interaction respectively. Reduced density gradient (RDG) graphs (Figure 9) indicated the presence of stronger stabilizing H-bonding (red region) interactions in both inclusion complexes. It is also observed from the RDG graphs that a significant amount of van der Waals attractive force (blue region) is responsible to stabilize both the inclusion complexes.