Journal of Theoretical and Computational Chemistry

CXCR4 is involved in inflammation, cancer metastasis and also HIV-1 entry into immune host cells. In the present research, it was decided to investigate the efficacy of some CXCR4 inhibitors from both pharmacokinetics and pharmacodynamics points of view. Quantitative structure–property relationship (QSPR) approach was applied to model the metabolic stability and instability of the compounds. Using QSPR modeling, it was tried to predict the metabolic stability using new hybrid algorithm which consisted of three different steps: descriptor reduction (PCA), stable–instable classification (KNN) and biological stability prediction (PLS). In the QSPR step, it is shown that the descriptor reduction (PCA) affects the result of the classification procedure (KNN). Besides, the obtained QSPR model can predict the metabolic stability of the stable compounds with $R^2$ of 0.98 for train data and of 0.64 for test data. In other words, increment and decrement of stability were followed by the model. Molecular docking simulation was exploited to define the essential interactions of an effective inhibitor with CXCR4 receptor.

The interaction between a single atom and graphene is an example in which the density functional theory (DFT) presents serious difficulties in giving an appropriate description of the adsorbate–substrate interaction, giving also different predictions according to the chosen approximation. The present calculations sustain that the inclusion of dispersion interactions in the framework of DFT for the Al/graphene system lead to potential energy curves of different nature according to the theoretical approach employed. The adsorption of an Al atom on the graphene surface was studied using both cluster and slab models. Cluster DFT–PBE calculations show the presence of a minimum at hollow site at an Al–graphene distance of about 2.1–2.3 Å corresponding to an exothermic state. Conversely, under B3LYP the same adsorption mode is endothermic. In comparison, our MP2 reference calculations predict the formation of two minima, both of exothermic nature, separated by an important energy barrier (about 0.2–0.4eV). The incorporation of empirical van der Walls (vdW) corrections to B3LYP changes the original behavior, giving an exothermic adsorption; furthermore, it produces a second, more external minimum. Slab calculations with PBE, and specially using the vdW-DF2 functional, predict also the formation of a minimum of very low depth at about 3.1 Å. The analysis of results obtained with cluster and slab models sustains that the bonding of the inner minima is of ionic character while that of the external ones is of dispersion character.

Modeling unfolded states of proteins has implications for protein folding and stability. Since in unfolded state proteins adopt multiple conformations, any experimentally measured quantity is ensemble averaged, therefore the computed quantity should be ensemble averaged as well. Here, we investigate the possibility that one can model an unfolded state ensemble with the coil model approach, algorithm such as “flexible-meccano” [Ozenne V et al., Flexible-meccano: A tool for the generation of explicit ensemle descriptions of intrinsically disordered proteins and their associated experimental observables, Bioinformatics 28:1463–1470, 2012], developed to generate structures for intrinsically disordered proteins. We probe such a possibility by using generated structures to calculate pKas of titratable groups and compare with experimental data. It is demonstrated that even with a small number of representative structures of unfolded state, the average calculated pKas are in very good agreement with experimentally measured pKas. Also, predictions are made for titratable groups for which there is no experimental data available. This suggests that the coil model approach is suitable for generating 3D structures of unfolded state of proteins. To make the approach suitable for large-scale modeling, which requires limited number of structures, we ranked the structures according to their solvent accessible surface area (SASA). It is shown that in the majority of cases, the top structures with smallest SASA are enough to represent unfolded state.

The surface protein of Influenza virus, Neuraminidase (NA), is believed to play a critical role in the release of new viral particle and thus spreads infection. It has been recognized as a valid drug target for anti-influenza therapy. Despite the number of available approved drugs for the influenza infection treatment, the emergence of resistant variants with novel mutations are the foremost challenges for the currently used NA inhibitors. Thus, the current investigation was carried out to ascertain potent inhibitors using computational strategies such as e-pharmacophore based virtual screening and docking approach. A three-dimensional e-pharmacophore hypothesis was generated based on the chemical features of complexes of the drugs and NA protein using PHASE module of Schrödinger suite. The generated hypothesis consisted of one hydrogen bond acceptor (A), two hydrogen bond donors (D), one negatively charged group (N) and one aromatic ring (R), ADDNR. The hypothesis was further evaluated for its integrity using enrichment analysis and used to filter out molecules with similar pharmacophoric features from approved, investigational and experimental subsets of DrugBank and ZINC database. In addition, ligand filtration was performed to curb down the molecules to an efficient collection of hit molecules by using Lipinski “rule of five and ADME analysis by using Qikprop module. Overall, the results from our analysis suggest that compound lisinopril and formoterol could serve as potent antiviral compounds for the treatment of influenza A virus infection. It is worth mentioning that the results correlate well with literature evidences.

The electronic structure and the nonlinear optical (NLO) properties of a series of platinum-sensitized dithienylethenes (DTEs) were investigated by using the density functional theory (DFT) method. DFT calculations reveal that the second-order NLO properties of complexes significantly increase with the DTE ligand being directly linked with terpyridine–Pt(II) complexes. Due to the good $\pi$-conjugated characteristics, closed-ring complexes possess much larger second-order NLO properties than the corresponding open-ring complexes. The computational ${\beta }_{\mathrm{\text{tot}}}$ values are in the order of 3c ($894.8\times 10^{-30}$ esu) $>$ 3o ($174.4\times 10^{-30}$ esu) $>$ 4c ($27.2\times 10^{-30}$ esu) $\approx$ 4o ($27.2\times 10^{-30}$ esu) $>$ 1 ($19.9\times 10^{-30}$ esu) $>$ 2c ($9.4\times 10^{-30}$ esu) $>$ 2o ($3.1\times 10^{-30}$ esu). Among all calculated platinum-sensitized dithienylethenes, 3c has the largest second-order NLO properties. The 4c and 4o have almost the same ${\beta }_{\mathrm{\text{tot}}}$ values and the ${\beta }_{\mathrm{\text{tot}}}$ value of 4o is slightly larger than that of 2o because the ether bonds can significantly prevent charge transfer within the complexes.

A theoretical investigation on the reactions of 1, 3, 5-trihydroxybenzene (PG) and 2, 4, 6-trihydroxyacetophenone (ACPG) with ^•OOH has been performed with the aim of elucidating the peroxyl radical scavenging properties of PG and its acylated derivative. The study has considered the hydrogen atom transfer (HAT), the single electron transfer-proton transfer and the sequential proton loss-electron transfer mechanisms and determined the geometric, energetic and electronic properties of the reaction species as well as the kinetic parameters for the HAT mechanism. DFT/M06-2X, DFT/MPW1K and DFT/BHHLYP calculation methods have been utilized in combination with the 6-311++G(3df, 2p) basis set. The DFT methods were benchmarked using the CBS-QB3 method. Thermodynamic parameters such as bond dissociation enthalpy (BDE) and ionization energy suggest that the thermodynamically preferred mechanism is the HAT mechanism. The geometric, electronic and energetic parameters suggest that the preferred site for the abstraction of the free phenolic H atom in ACPG is the ortho position. Spin density and branching ratio values indicate that the most stable and preferable product formed is for the reaction of ACPG $+$ ^•OOH at the ortho position. The estimated rate constants obtained indicate that the reaction of ACPG $+$ ^•OOH is kinetically preferred to the reaction of PG $+$ ^•OOH, which is in agreement with experimental findings.