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Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated via the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed via free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design., Competing Interests: There are no conficts to declare., (This journal is © The Royal Society of Chemistry.)

Developing low-cost and highly effective adsorbent materials to decolorate wastewater is still challenging in the industry. In this study, TiO 2 -modified Al 2 O 3 microspheres with different TiO 2 contents were produced by spray pyrolysis, which is rapid and easy to scale up. Results reveal that the modification of γ-Al 2 O 3 with TiO 2 reduced the crystallite size of Al 2 O 3 and generated more active sites in the composite sample. The as-synthesized Al 2 O 3 -TiO 2 microspheres were applied to remove anionic methyl orange (MO) and cationic rhodamine B (RB) dyes in an aqueous solution using batch and continuous flow column sorption processes. Results show that the Al 2 O 3 microspheres modified with 15 wt% of TiO 2 exhibited the maximum adsorbing capacity of ∼41.15 mg g -1 and ∼32.28 mg g -1 for MO and RB, respectively, exceeding the bare γ-Al 2 O 3 and TiO 2 . The impact of environmental complexities on the material's reactivity for the organic pollutants was further delineated by adjusting the pH and adding coexisting ions. At pH ∼5.5, the TiO 2 /Al 2 O 3 microspheres showed higher sorption selectivity towards MO. In the continuous flow column removal, the TiO 2 /Al 2 O 3 microspheres achieved sorption capacities of ∼31 mg g -1 and ∼19 mg g -1 until the breakthrough point for MO and RB, respectively. The findings reveal that TiO 2 -modified Al 2 O 3 microspheres were rapidly prepared by spray pyrolysis, and they effectively treated organic dyes in water in batch and continuous flow removal processes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Oxoberberine (OB, 2,10-dihydroxy-3,9-dimethoxy-8-oxo-protoberberine, artathomsonine), which was isolated from Artabotrys thomsonii, was shown to exhibit potent antioxidant activity in vitro , however that is the only reported evidence of the radical scavenging activity of this compound thus far. In the present study, thermodynamic and kinetic calculations were used to determine the free radical scavenging activity of OB against a range of biologically important species, under physiological conditions. In the first part the activity is calculated against the HOO˙ radical that is both biologically important and a reference radical for comparison. It was found that OB has high antiradical capacity against HOO˙ in both lipid medium and water at physiological pH with k overall = 1.33 × 10 5 and 1.73 × 10 6 M -1 s -1 , respectively. The formal hydrogen transfer mechanism defined the activity in nonpolar environments, whereas in the aqueous solution the single electron transfer competes with the hydrogen transfer pathway. The results showed that, in lipid medium, the HOO˙ trapping capability of OB is better than typical antioxidants such as Trolox, BHT, resveratrol and ascorbic acid. Similarly, the activity of OB in water at pH 7.4 is roughly 19 and 7 times faster than those of Trolox and BHT, respectively, but slightly lower than the activities of resveratrol or ascorbic acid. In the second part, it was found that OB also exhibits high activity against other typical free radicals such as CH 3 O˙, CH 3 OO˙, CCl 3 OO˙, NO 2 , SO 4 ˙ - , DPPH and ABTS˙ + with k f ranging from 2.03 × 10 5 to 5.74 × 10 7 M -1 s -1 . Hence, it is concluded that OB is a promising radical scavenger in the physiological environment., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Direct and indirect antioxidant activities of rosmarinic acid (RA) based on HOO˙/CH 3 OO˙ radical scavenging and Fe(iii)/Fe(ii) ion chelation were theoretically studied using density functional theory at the M05-2X/6-311++G(2df,2p) level of theory. First, four antioxidant mechanisms including hydrogen atom transfer (HAT), radical adduct formation (RAF), proton loss (PL) and single electron transfer (SET) were investigated in water and pentyl ethanoate (PEA) phases. Regarding the free radical scavenging mechanism, HAT plays a decisive role with overall rate coefficients of 1.84 × 10 3 M -1 s -1 (HOO˙) and 4.49 × 10 3 M -1 s -1 (CH 3 OO˙) in water. In contrast to PL, RAF and especially SET processes, the HAT reaction in PEA is slightly more favorable than that in water. Second, the [Fe(iii)(H 2 O) 6 ] 3+ and [Fe(ii)(H 2 O) 6 ] 2+ ion chelating processes in an aqueous phase are both favorable and spontaneous especially at the O5, site-1, and site-2 positions with large negative Δ r G 0 values and great formation constant K f . Finally, the pro-oxidant risk of RA - was also considered via the Fe(iii)-to-Fe(ii) complex reduction process, which may initiate Fenton-like reactions forming reactive HO˙ radicals. As a result, RA - does not enhance the reduction process when ascorbate anions are present as reducing agents, whereas the pro-oxidant risk becomes remarkable when superoxide anions are found. The results encourage further attempts to verify the speculation using more powerful research implementations of the antioxidant activities of rosmarinic acid in relationship with its possible pro-oxidant risks., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The spread of severe acute respiratory syndrome coronavirus 2 novel coronavirus (SARS-CoV-2) worldwide has caused the coronavirus disease 2019 (COVID-19) pandemic. A hundred million people were infected, resulting in several millions of death worldwide. In order to prevent viral replication, scientists have been aiming to prevent the biological activity of the SARS-CoV-2 main protease (3CL pro or Mpro). In this work, we demonstrate that using a reasonable combination of deep-learning calculations and atomistic simulations could lead to a new approach for developing SARS-CoV-2 main protease (Mpro) inhibitors. Initially, the binding affinities of the natural compounds to SARS-CoV-2 Mpro were estimated via atomistic simulations. The compound tomatine, thevetine, and tribuloside could bind to SARS-CoV-2 Mpro with nanomolar/high-nanomolar affinities. Secondly, the deep-learning (DL) calculations were performed to chemically alter the top-lead natural compounds to improve ligand-binding affinity. The obtained results were then validated by free energy calculations using atomistic simulations. The outcome of the research will probably boost COVID-19 therapy., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3- O -(6- O -α-l-arabinopyranosyl)-β-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 ( wailupemycins H ), M11 (cottoquinazolines B), and M9 ( wailupemycins I ) adopted the predicted ligand-binding free energy of -9.87, -9.82, -9.62, and -9.35 kcal mol -1 , respectively, whereas the other adopted predicted ligand-binding free energies in the range from -8.54 to -8.94 kcal mol -1 . The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Antioxidant and UV absorption activities of three aaptamine derivatives including piperidine[3,2- b ]demethyl(oxy)aaptamine (C1), 9-amino-2-ethoxy-8-methoxy-3 H -benzo[de][1,6]naphthyridine-3-one (C2), and 2-( sec -butyl)-7,8-dimethoxybenzo[de]imidazo[4,5,1- ij ][1,6]-naphthyridin-10(9 H )-one (C3) were theoretically studied by density functional theory (DFT). Direct antioxidant activities of C1-C3 were firstly evaluated via their intrinsic thermochemical properties and the radical scavenging activity of the potential antioxidants with the HOO˙/HO˙ radicals via four mechanisms, including: hydrogen atom transfer (HAT), single electron transfer (SET), proton loss (PL) and radical adduct formation (RAF). Kinetic calculation reveals that HOO˙ scavenging in water occurs via HAT mechanism with C1 ( k app , 7.13 × 10 6 M -1 s -1 ) while RAF is more dominant with C2 ( k app , 1.40 × 10 5 M -1 s -1 ) and C3 ( k app , 2.90 × 10 5 M -1 s -1 ). Antioxidant activity of aaptamine derivatives can be classified as C1 > C3 > C2. Indirect antioxidant properties based on Cu(i) and Cu(ii) ions chelating activity were also investigated in aqueous phase. All three studied compounds show spontaneous and favorable Cu(i) ion chelating activity with Δ G 0 being -15.4, -13.7, and -15.7 kcal mol -1 , whereas Δ G 0 for Cu(ii) chelation are -10.4, -10.8, and -2.2 kcal mol -1 for C1, C2 and C3, respectively. In addition, all compounds show UVA and UVB absorption; in which the excitations are determined mostly as π-π* transition. Overall, the results suggest the potential applications of the aaptamines in pharmaceutics and cosmetics, i.e. as a sunscreen and antioxidant ingredient., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Fraxin (FX) (7-hydroxy-6-methoxycoumarin 8-glucoside) is a typical natural product of the coumarin family. This compound was shown to protect endothelial cells from oxidative stress; however, the nature of its antioxidant properties is still ambiguous. In this study, we report on a systematic evaluation of the radical scavenging activity of FX using a two-tier protocol based on thermodynamic and kinetic calculations. The results show that FX has moderate activity in the aqueous physiological environment against a range of radicals including HO˙, CCl 3 O˙, CCl 3 OO˙, NO 2 , , and HOO˙. The latter was examined in detail due to the prevalence of HOO˙ as a source of oxidative stress in biological systems. HOO˙ scavenging activity was promising in the gas phase but low in physiological environments with k overall = 1.57 × 10 6 , 3.13 × 10 2 and 2.68 × 10 3 M -1 s -1 in the gas phase, pentyl ethanoate and water solvents, respectively. The formal hydrogen transfer mechanism at the O7-H bond dominates the hydroperoxyl radical scavenging of FX in the nonpolar media, whereas, in the polar environment, the activity is exerted by the single electron transfer mechanism of the anion state. This activity falls behind typical antioxidants such as Trolox, ascorbic acid, and trans -resveratrol under the studied conditions. Thus FX may have multiple health benefits, but it is not an outstanding natural antioxidant., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. In this context, our study has revealed that in silico screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the Mpro instead of the dimeric one. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 24 compounds. The obtained results were also confirmed via binding pose and noncovalent contact analyses. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein, a novel fluorescent sensor has been developed for the detection of biothiols based on theoretical calculations of the stability constant of the complex between a Cu 2+ ion and ( E )-3-((2-(benzo[ d ]thiazol-2-yl)hydrazono)methyl)-7-(diethylamino) coumarin (BDC) as a fluorescent ligand. In this study, on the basis of density functional theory method, the Gibbs free energy of ligand-exchange reaction and the solvation model were carried out using thermodynamic cycles. The obtained results are in good agreement with the experimental data. The BDC-Cu 2+ complex can be used as a fluorescent sensor for the detection of biothiols in the presence of non-thiol containing amino acids, with a detection limit for cysteine at 0.3 μM. Moreover, theoretical calculations of excited states were used to elucidate variations in the fluorescence properties. The computed results show that the excited doublet states D 2 and D 1 are dark doublet states, which quench the fluorescence of the complex., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ribavirin and remdesivir have been preclinically reported as potential drugs for the treatment of SARS-CoV-2 infection, while light silver tetrylene complexes (NHE Ph -AgCl and (NHE Ph -AgCl) 2 with E = C, Si, and Ge) have gained significant interest due to their promising applicability on the cytological scale. Firstly, the structures and bonding states of silver-tetrylene complexes (NHE-Ag) and bis-silver-tetrylene complexes (NHE-Ag-bis) were investigated using density functional theory (DFT) at the BP86 level with the def2-SVP and def2-TZVPP basis sets. Secondly, the inhibitory capabilities of the carbene complexes (NHC-Ag and NHC-Ag-bis) and the two potential drugs (ribavirin and remdesivir) on human-protein ACE2 and SARS-CoV-2 protease PDB6LU7 were evaluated using molecular docking simulation. The carbene ligand NHC bonds in a head-on configuration with AgCl and (AgCl) 2 , whereas, the other NHE (E = Si and Ge) tetrylene ligands bond in a side-on mode to the metal fragments. The bond dissociation energy (BDE) of the NHE-Ag bond in the complex families follows the order of NHC-Ag > NHSi-Ag > NHGe-Ag and NHSi-Ag-bis > NHGe-Ag-bis > NHC-Ag-bis. The natural bond orbital analysis implies that the [NHE Ph →AgCl] and [(NHE Ph ) 2 →(AgCl) 2 ] donations are derived mainly from the σ- and π-contributions of the ligands. The docking results indicate that both the ACE2 and PDB6LU7 proteins are strongly inhibited by silver-carbene NHC-Ag, bis-silver-carbene NHC-Ag-bis, ribavirin, and remdesivir with the docking score energy values varying from -17.5 to -16.5 kcal mol -1 and -16.9 to -16.6 kcal mol -1 , respectively. The root-mean-square deviation values were recorded to be less than 2 Å in all the calculated systems. Thus, the present study suggests that silver-carbene NHC-Ag and bis-silver-carbene NHC-Ag-bis complexes are potential candidates to inhibit ACE2 and PDB6LU7, and thus potentially conducive to prevent infection caused by the SARS-CoV-2 virus., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)