Antibodies as Carrier Molecules: Encapsulating Anti-Inflammatory Drugs inside Herceptine

The human epidermal growth factor receptor 2 (HER2) is overexpressed in about a third of breast cancer patients, with a strong involvement of the cyclooxygenase-2 (COX-2) enzyme in the tumor progress. HER2 and COX-2 are consequently potential targets for inhibiting carcionogenesis. Herceptin (trastuzumab) is an antibody that partially blocks HER2-positive cancers at their initial stage. Unfortunately, the overall response rate to the single treatment with this antibody is still modest, and therefore, it needs to be improved by combining several chemotherapeutic agents. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs) are designed to halt COX-2 functionality, so they might also exhort an anticancer activity. In this contribution, dual Herceptin–NSAID drugs are designed using theoretical tools. More specifically, blind docking, molecular dynamics, and quantum calculations are performed to assess the stability of 14 NSAIDs embedded inside Herceptin. Our calculations reveal the feasibility of improving the antitumor activity of the parent Herceptin by designing a dual HER2-targeting with Etofenamate. That coupling mode might be used to further rationalize new clinical strategies beyond classical antibody dosages

Structure, Spectra, and DFT Simulation of Nickel Benzazolate Complexes with Tris(2-aminoethyl)amine Ligand

Benzazolate complexes of Ni­(II), [Ni­(pbz)­(tren)]­ClO₄ (pbz = 2-(2′-hydroxyphenyl)-benzimidazole (pbm), <b>1</b>, 2-(2′-hydroxyphenyl)-benzoxazole (pbx), <b>2</b>, 2-(2′-hydroxyphenyl)-benzothiazole (pbt), <b>3</b>; tren = tris­(2-aminoethyl)­amine), are prepared by self-assembly reaction and structurally characterized. Theoretical DFT simulations are carried out to reproduce the features of their crystal structures and their spectroscopic and photophysic properties. The three complexes are moderately luminescent at room temperature both in acetonitrile solution and in the solid state. The simulations indicate that the absorption spectrum is dominated by two well-defined transitions, and the electronic density concentrates in three MOs around the benzazole ligands. The Stokes shifts of the emission spectra of complexes <b>1</b>–<b>3</b> are determined by optimizing the electronic excited state

Erratum: Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures

Erratum: Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperature

Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures

When large structural displacements take place between the ground state (GS) and excited state (ES) minima of polyatomic molecules, the choice of a proper set of coordinates can be crucial for a reliable simulation of the vibrationally resolved absorption spectrum. In this work, we study two carotenoids that undergo structural displacements from GS to ES minima of different magnitude, from small displacements for violaxanthin to rather large ones for β-carotene isomers. Their finite-temperature (77 and 300 K) spectra are simulated at the harmonic level, including Duschinsky effect, by time-dependent (TD) and time-independent (TI) approaches, using (TD)­DFT computed potential energy surfaces (PES). We adopted two approaches to construct the harmonic PES, the Adiabatic (AH) and Vertical Hessian (VH) models and, for AH, two reference coordinate frames: Cartesian and valence internal coordinates. Our results show that when large displacements take place, Cartesian coordinates dramatically fail to describe curvilinear displacements and to account for the Duschinsky matrix, preventing a realistic simulation of the spectra within the AH model, where the GS and ES PESs are quadratically expanded around their own equilibrium geometry. In contrast, internal coordinates largely amend such deficiencies and deliver reasonable spectral widths. As expected, both coordinate frames give similar results when small displacements occur. The good agreement between VH and experimental line shapes indicates that VH model, in which GS and ES normal modes are both evaluated at the GS equilibrium geometry, is a good alternative to deal with systems exhibiting large displacements. The use of this model can be, however, problematic when imaginary frequencies arise. The extent of the nonorthogonality of the Dushinsky matrix in internal coordinates and its correlation with the magnitude of the displacement of the GS and ES geometries is analyzed in detail

DFT Simulation of Structural and Optical Properties of 9‑Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru­(II) anticancer agent and two new closely related Rh­(III) and Ir­(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl₃) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices

DFT Simulation of Structural and Optical Properties of 9‑Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru­(II) anticancer agent and two new closely related Rh­(III) and Ir­(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl₃) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices

Conformational Changes of Trialanine in Water Induced by Vibrational Relaxation of the Amide I Mode

Most of the protein-based diseases are caused by anomalies in the functionality and stability of these molecules. Experimental and theoretical studies of the conformational dynamics of proteins are becoming in this respect essential to understand the origin of these anomalies. However, a description of the conformational dynamics of proteins based on mechano-energetic principles still remains elusive because of the intrinsic high flexibility of the peptide chains, the participation of weak noncovalent interactions, and the role of the ubiquitous water solvent. In this work, the conformational dynamics of trialanine dissolved in water (D₂O) is investigated through Molecular Dynamics (MD) simulations combined with instantaneous normal modes (INMs) analysis both at equilibrium and after the vibrational excitation of the C-terminal amide I mode. The conformational equilibrium between α and pPII conformers is found to be altered by the intramolecular relaxation of the amide I mode as a consequence of the different relaxation pathways of each conformer which modify the amount of vibrational energy stored in the torsional motions of the tripeptide, so the α → pPII and pPII → α conversion rates are increased differently. The selectivity of the process comes from the shifts of the vibrational frequencies with the conformational changes that modify the resonance conditions driving the intramolecular energy flows

Structure and Spectroscopic Properties of Nickel Benzazolate Complexes with Hydrotris(pyrazolyl)borate Ligand

The reaction of benzazole ligands 2-(2′-hydroxylphenyl)­benzimidazole (Hpbm), 2-(2′-hydroxylphenyl)­benzoxazole (Hpbx), and 2-(2′-hydroxylphenyl)­benzothiazole (Hpbt), with [Ni­(Tp*)­(μ-OH)]₂ (Tp* = hydrotris­(3,5-dimethylpyrazolyl)­borate), leads to pentacoordinate nickel complexes [Ni­(Tp*)­(pbz)] (pbz = pbm (<b>1</b>), pbx (<b>2</b>), pbt (<b>3</b>)). The structures of <b>1</b>, <b>2</b>, and <b>3</b> were determined by X-ray crystallography. The pentacoordinate nickel complexes have distorted trigonal bipyramidal geometries with Addison’s τ parameter values of 0.63, 0.73, and 0.61 for <b>1</b>, <b>2</b> and <b>3</b>, respectively. The benzazolates are bonded in an η²(N,O) fashion to the nickel atoms. DFT calculations are carried out to optimize the structures of the three complexes giving a good agreement with the X-ray structures. The ¹H NMR spectra of complexes <b>1</b>–<b>3</b> exhibit sharp isotropically shifted signals. The complete assignment of these signals required an application of two-dimensional {¹H–¹H}-COSY techniques. The experimental absorption spectra of the three complexes in chloroform solution each show an intense absorption band in the ultraviolet region ca. 240 nm, followed by three less intense bands, the first two at ∼295 and ∼340 nm, and the last more disperse one, at wavelengths between 360 and 410 nm. The absorption spectra are simulated by TD-DFT and reproduce the main features of the experimental spectra well. The analysis of the electronic transitions by inspection of the frontier molecular orbitals and also the natural transition orbitals allowed us to characterize and assign the observed bands properly. The three complexes are moderately blue luminescent at room temperature, both in the solid state and in solution. Emission spectra at room temperature display broad structureless bands in chloroform solution at 460, 482, and 512 nm for complexes <b>1</b>, <b>2</b> and <b>3</b>, respectively, and structured emission in solid state with λ_max values of 473, 486, and 516 nm. Complexes containing different donor atoms in the benzazole ligand are furthermore observed to give different luminescence responses in the presence of Zn­(II), Cd­(II), Hg­(II), and Cu­(II)