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Cancer remains a serious health concern representing one of the leading causes of deaths worldwide. The enzyme human carbonic anhydrase IX (hCA IX) is found to be over-expressed in many cancer types and its selective inhibition over its cytosolic off-target isoform, human carbonic anhydrase II (hCA II), represents a potential area of research in the development of novel anticancer compounds. This work is concerned with the use of various in silico tools for the identification of natural product based molecules that can selectively inhibit hCA IX over hCA II. MM-GBSA assisted structure-based virtual screening against hCA IX was performed for nearly 225,000 natural products imported from the ZINC15 database. The obtained hits were checked for their potency by considering acetazolamide, the bound inhibitor of hCA IX, as the reference molecule, and 121 molecules were identified as potent hCA IX inhibitors. After ensuring their potency, cross-docking, followed by MM-GBSA calculations of the hits with hCA II, was performed, and their selectivity was assessed by considering the hCA IX selective compound SLC-0111 as the reference molecule, and 50 natural products were identified as potent as well as selective hCA IX inhibitors. Molecules with the quinoline scaffold showed the highest selectivity, and their selectivity was attributed to the strong electrostatic interactions of the zinc binding group (ZBG) with the active site Zn(II) ion. Furthermore, the stability of the binding modes of the top hCA IX selective hits was ensured by performing molecular dynamics (MD) simulations, which clearly proved that one of the short-listed molecules is truly selective, as it does not interact with the active site Zn(II) ion of hCA II, but interacts strongly with this ion in hCA IX. Bonding pose metadynamics studies revealed that the ligand moves to a more stable binding site from the one predicted by the docking studies and shows stronger interaction with the protein and Zn(II) at this binding site. The ligand is not likely to have issues with bioavailability. As a result, this ligand can be taken for bioassay testing and subsequently used as a feasible therapeutic treatment for a variety of cancer types. Communicated by Ramaswamy H. Sarma.

Human carbonic anhydrase IX (hCA IX) is a promising target for the development of potential anticancer agents. In the current study, pharmacophore and 3D-QSAR models have been developed using SLC-0111 derivatives. The developed models have been further utilized for the virtual screening process to develop potent hCA IX inhibitors. Thirteen different models have been developed by employing various combinations of training and test set molecules. Based on this, a model, AADDR.135, comprising two H-bond acceptors, two H-bond donors and one aromatic ring, has been found as the best QSAR model. The proposed model exhibits high robustness ( R 2 = 0.9789), with good predictive ability ( Q 2 = 0.6872). An external library of drug-like compounds (∼10000 molecules) imported from the ZINC15 database has been screened over the model AADDR.135. In total, 1601 compounds were obtained as hits. Molecular docking studies and molecular dynamics simulations have been performed on the obtained hits and, based on these computations, two unique molecules have been identified as potential hCA IX inhibitors. These show higher binding energies compared to the parent molecule and its most potent analogue.Communicated by Ramaswamy H. Sarma.

We have investigated the active site of E. coli MurB using the Quantum Mechanics/Molecular Mechanics (QM/MM) methodology. The docking of three novel series of 4-thiazolidinone derivatives has been performed using two methods: rigid docking and flexible docking (Induced Fit Docking: IFD). The results have been compared to understand the conformational aspects of the enzyme. The docking results from rigid docking show that the ligands with highly negative ΔG bind have poor docking scores. In addition, the value of the regression coefficient ( R ) obtained on correlating the ΔG bind and the experimental pMIC values is insignificant. On keeping the protein flexible, there is a remarkable improvement in both the docking score and ΔG bind , along with a good value of R (0.64). Two important residues, Tyr254 and Try190 are found to be highly displaced during the flexible docking and hence their role in effective ligand binding has been confirmed. Thus, comparing the two methodologies, IFD has emerged as the more appropriate one for studying the E. coli MurB enzyme. To further substantiate the findings, MD studies over a time period of 20 ns have been performed on the IFD-LIII j and Rigid/XP-LIII j complexes and the results shows the former complex to be more stable, with lower average RMSD and higher average ΔG bind . Communicated by Ramaswamy H. Sarma.

Polyphenolic compounds are known to exhibit potent antioxidant properties owing to the presence of various phenolic groups. The present study reports the antioxidant potentials of six retrochalcones, namely echinatin, and licochalcone A, B, C, D and E, isolated from the root of the Glycyrrhiza species, toward various reactive oxygen and nitrogen species. Different mechanistic pathways, viz. hydrogen atom transfer (HAT), single electron transfer (SET), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), have been considered. In addition, two other pathways, i.e. sequential double proton loss electron transfer (SdPLET) and sequential proton loss hydrogen atom transfer (SPLHAT), which are significant for the scavenging of reactive species by the mono-deprotonated forms of retrochalcones, have also been considered. All the calculations were performed using density functional theory at the B3LYP/6-311++G** level in the gas phase and in aqueous solution. The results suggest the predominance of the HAT mechanism in the gas phase, while in aqueous solution, the SPLET mechanism is thermodynamically favored. The possibility of SdPLET increases at higher pH., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The antioxidant properties of echinatin (Ech), isolated from liquorice, have recently been reported. It is well known that the free radical species can be deactivated by phenolic antioxidants via different mechanistic pathways. In this work, the scavenging of eighteen different reactive oxygen species (ROS) has been considered, focussing on three main working mechanisms, namely hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). The investigations have been performed in different dielectric media, viz. gas phase, benzene, methanol and aqueous solution, using density functional theory (DFT) calculations at the M05-2X/6-311++G** level. Various molecular descriptors have been elucidated for Ech as well as the ROS and compared with the reference antioxidant molecule, trolox. In addition, the redox potentials and the equilibrium constants have been calculated to discuss the feasibility of the overall scavenging process. The results demonstrate that the 4-OH group is the first site for H-atom donation, followed by 4'-OH. Further, it has been found that HAT would be the most favourable mechanism in the gas phase. The SPLET mechanism is thermodynamically favoured in polar media like water and methanol, while in the case of non-polar solvents like benzene, the two mechanisms are observed to be competitive.

Histone deacetylases (HDACs) play important roles in various biological processes, but are also notorious for their over-expression in numerous cancers and neurological disorders. Therefore, the development of isoform selective HDAC inhibitors is crucial in order to prevent any side effects of pan inhibition. This work focuses on identifying novel inhibitors for the selective inhibition of HDAC8, an isoform implicated in fatal diseases like T-cell lymphoma, colon cancer and childhood neuroblastoma. Virtual screening of the 'In-trials' subset of ZINC database has been carried out with the help of two pharmacophore models signifying potent and selective HDAC8 inhibition. A detailed molecular docking strategy, followed by molecular dynamics simulations and post-scoring with MM-GBSA calculations, has led to the identification of six promising molecules that have excellent binding with the HDAC8 active site. In order to establish the selectivity profile of these molecules, their binding to off-target HDAC isoforms has also been evaluated. Substitution analyses of the proposed inhibitors suggest that aromatic substituents that access the adjacent hydrophobic pocket of the HDAC8 active site have the potential to further enhance the HDAC8 selectivity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Despite significant advances in the development of highly efficient and robust oxygen evolution reaction (OER) electrocatalysts to replace noble-metal catalysts, commercializing OER catalysts with high catalytic activity for sustainable development still remains a great challenge. Especially, transition-metal Fe-based OER catalysts, despite their earth-abundant, cost-efficient, and environmentally benign superiorities over Co- and Ni-based materials, have received relatively insufficient attention because of their poor apparent OER activities. Herein, by rational design, we report Ni-modified pyrite (FeS 2 ) spheres with yolk-shell structure that could serve as pre-electrocatalyst precursors to induce a highly active nickel-iron oxyhydroxide via in situ electrochemical topological transformation under the OER process. Notably, as confirmed by the results of X-ray absorption spectroscopy, X-ray photoelectron spectroscopy, and density functional theory (DFT) calculations, Ni doping could effectively regulate the intrinsic electronic structure of FeS 2 to realize a semiconductor-to-semimetal transition, which endows FeS 2 with dramatically improved conductivity and water adsorption ability, providing prequisites for subsequent topological transformation. Moreover, systematic post-characterizations further reveal that the optimal Ni-FeS 2 -0.5 sample completely converts to amorphous Ni-doped FeOOH via an in situ electrochemical transformation with yolk-shell structure well-preserved under the OER conditions. The electronic structure modulation combined with electrochemical topotactic transformation strategies well stimulate the reactive Fe sites in Ni-FeS 2 -0.5, which show impressively low overpotentials of 250 and 326 mV to drive the current densities ( j) of 10 and 100 mA cm -2 , respectively, and a Tafel slope as small as 34 mV dec -1 for the OER process. When assembled as a water electrolyzer for the overall water splitting, Ni-FeS 2 -0.5 can display a low voltage of 1.55 V to drive a current density of 10 mA cm -2 , outperforming most of the transition-metal-based bifunctional electrocatalysts to date. This work may provide new insight into the rational design of other high-performance Fe-based OER electrocatalysts and inspire the exploration of cost-effective, ecofriendly electrocatalysts to meet the demand for future sustainable development.

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

Peptide deformylase (PDF) has emerged as an important antibacterial drug target. Considerable effort is being directed toward developing peptidic and non-peptidic inhibitors for this metalloprotein. In this work, the known peptidic inhibitor BB-3497 and its various ionization and tautomeric states are evaluated for their inhibition efficiency against PDF using a molecular mechanics (MM) approach as well as a mixed quantum mechanics/molecular mechanics (QM/MM) approach, with an aim to understand the interactions in the binding site. The evaluated Gibbs energies of binding with the mixed QM/MM approach are shown to have the best predictive power. The experimental pose is found to have the most negative Gibbs energy of binding, and also the smallest strain energy. A quantum mechanical evaluation of the active site reveals the requirement of strong chelation by the ligand with the metal ion. The investigated ligand chelates the metal ion through the two oxygens of its reverse hydroxamate moiety, particularly the N-O(-) oxygen, forming strong covalent bonds with the metal ion, which is penta-coordinated. In the uninhibited state, the metal ion is tetrahedrally coordinated, and hence chelation with the inhibitor is associated with an increase of the metal ion coordination. Thus, the strong binding of the ligand at the binding site is accounted for.

In this work, polysorbate surfactants with same functional groups but with varying molecular masses (Tween-80, Tween-40 and Tween-20) in different concentrations (0.1% to 20% w/w) were used to study the effect of the length of the surfactant chain on the luminescence of the entrapped TOPO-capped CdSe nanocrystals. Various phospholipids with different functional headgroups such as ethylene glycol (-PEG) and amine (-NH2) were used to improve biocompatibility and provide sites for bioconjugation respectively. It is understood that that the hydrophobic ends of the surfactant binds with the water repelling groups of the cap layer, thus modifying the CdSe cap layer and making it soluble in aqueous media. It was observed that the PL emission intensity of CdSe increases with increase in concentration of Tween-series surfactant unlike in the case of thiol-coated CdSe nanoparticles. However, higher PL intensity was obtained in the case of stoichiometric CdSe with Tween-40 corresponding to 20% w/w. The efficient PL sustainability of water-soluble CdSe QD's can be attributed to the simpler chain structure of Tween-40 surfactant resulting in better passivation of the micelle.

The preparation of N-(p-ethylphenyl)thiobenzohydroxamic acid and its spectral properties are described in this paper. The preferred conformation of the acid is investigated by both infrared techniques and theoretical calculations at the DFT level. It is found that the acid exists in the cis thione (Z) form, rather than the trans form (E) in the gas phase. Both infrared spectroscopy and theoretical calculations show that this structure is stabilized by intramolecular hydrogen bonding.

The conformational preferences of thiohydroxamic acids (N-hydroxythioamides) are investigated by the density functional B3LYP/6-311++G(3df,3pd)//B3LYP/6-31G(d) method in this work. Unlike hydroxamic acids, the thione and thiol forms are found to be equally stable in the gas phase, and the reaction pathways for the interconversion between the thione and thiol forms have been deduced to involve rotation about the C[double bond, length as m-dash]N bond of the thiol tautomer in the rate-determining step. The effect of aqueous solvation on the reactions has also been investigated. It is found that inclusion of a few explicit water molecules in an implicit solvent calculation is necessary in order to accurately account for hydrogen bonding effects. Thiohydroxamic acids, like their hydroxamic acid analogues, are found to be N-acids, both in the gas phase and in aqueous solution.

The preparation of N-p-(ethylbenzene)thiobenzohydroxamic acid chelates with several metal ions and their spectral properties are described in this paper. This is followed by a theoretical study of metal complexes of some thiohydroxamic acids, as well as the prepared chelates. The electronic properties of the metal complexes are discussed. The experimental and theoretical electronic spectra are also compared. A possible reason for the smaller pKa values of thiohydroxamic acid complexes than those of the corresponding hydroxamic acids is given.