Rational design of pincer-nickel complexes for catalytic cyanomethylation of benzaldehyde: A systematic DFT study.

The current study dwells upon the efforts to computationally probe a phosphine-free pincer-nickel complex that would demonstrate an efficiency better than the reported phosphine-based pincer-nickel complex (iPr2 POCNEt2 )Ni(CH2 CN) for cyanomethylation reaction. For this purpose, the mechanism of cyanomethylation of benzaldehyde was studied quantum mechanically for a series of 11 pincer-nickel complexes. The energetics of various intermediates and transition states involved in the catalytic cycle for each catalyst was compared with the corresponding energetics of the Miller's catalyst (iPr2 POCNEt2 )Ni(CH2 CN) that is reported to accomplish the cyanomethylation at room temperature. While pincer complexes (iPr4 NNN)Ni(CH2 CN) and (iPr4 NCN)Ni(CH2 CN) containing strong σ-donating amines were found to fare poorly, pincer-nickel complexes (iPr2 NCN)Ni(CH2 CN) and (dm PheboxNCN)Ni(CH2 CN) based on weaker σ-donating imines had energetics more favorable than the reported efficient catalyst (iPr2 POCNEt2 )Ni(CH2 CN). While strong trans-influencing C as the pincer central atom was found to be pivotal for lowering the cyanomethylation kinetics, presence of a poor trans-influencing N proved to be detrimental on the overall energetics.

Modeling antimalarial and antihuman African trypanosomiasis compounds: a ligand- and structure-based approaches.

This study examines the interaction of 137 antimalarial and antihuman African trypanosomiasis compounds [bis(2-aminoimidazolines), bisguanidinediphenyls and polyamines] on three different in vitro assays (Trypanosoma brucei rhodesiense (T.b.r.), Plasmodium falciparum (P.f.) and cytotoxicity-L6 cells). ΔTm values, wherever available, were also examined for the considered ligands. Eight DNA-ligand complexes and one DNA structure without ligand were selected from protein data bank (PDB) based on the structural similarity. Geometry optimization of all the considered ligands was carried out at the B3LYP/6-31G(d) level of theory. The AutoDock4 tool was utilized for the docking of these molecules at the minor groove of nine selected DNA crystal structures. We observed DT20, DA6, DT8 and DT19 residues generally interact with most of the considered ligands. Molecular dynamics simulations, molecular mechanics-generalized born surface area and molecular mechanics-Poisson Boltzmann surface area calculations indicate that the docked poses are generally stable and docked ligands do not show much deviation in the minor groove of DNA until 10 ns simulation. Efficient and statistically significant quantitative structure-activity relationship models for T.b.r., P.f., C-L6 and ΔTm values were developed. All the generated models are internally and externally validated. We predicted a few ligands with significant IC50 values against P.f. based on the developed models. These results may help to design new and potent antimalarial and antihuman African trypanosomal compounds.

Benchmarking of different molecular docking methods for protein-peptide docking.

BACKGROUND: Molecular docking studies on protein-peptide interactions are a challenging and time-consuming task because peptides are generally more flexible than proteins and tend to adopt numerous conformations. There are several benchmarking studies on protein-protein, protein-ligand and nucleic acid-ligand docking interactions. However, a series of docking methods is not rigorously validated for protein-peptide complexes in the literature. Considering the importance and wide application of peptide docking, we describe benchmarking of 6 docking methods on 133 protein-peptide complexes having peptide length between 9 to 15 residues. The performance of docking methods was evaluated using CAPRI parameters like FNAT, I-RMSD, L-RMSD. RESULT: Firstly, we performed blind docking and evaluate the performance of the top docking pose of each method. It was observed that FRODOCK performed better than other methods with average L-RMSD of 12.46 Å. The performance of all methods improved significantly for their best docking pose and achieved highest average L-RMSD of 3.72 Å in case of FRODOCK. Similarly, we performed re-docking and evaluated the performance of the top and best docking pose of each method. We achieved the best performance in case of ZDOCK with average L-RMSD 8.60 Å and 2.88 Å for the top and best docking pose respectively. Methods were also evaluated on 40 protein-peptide complexes used in the previous benchmarking study, where peptide have length up to 5 residues. In case of best docking pose, we achieved the highest average L-RMSD of 4.45 Å and 2.09 Å for the blind docking using FRODOCK and re-docking using AutoDock Vina respectively. CONCLUSION: The study shows that FRODOCK performed best in case of blind docking and ZDOCK in case of re-docking. There is a need to improve the ranking of docking pose generated by different methods, as the present ranking scheme is not satisfactory. To facilitate the scientific community for calculating CAPRI parameters between native and docked complexes, we developed a web-based service named PPDbench ( http://webs.iiitd.edu.in/raghava/ppdbench/ ).

Geometry-Driven Iminosemiquinone Radical to Cu(II) Electron Transfer and Stabilization of an Elusive Five-Coordinate Cu(I) Complex: Synthesis, Characterization, and Reactivity with KO2.

The noninnocent ligand H2LAP(Ph) contained a bulky phenyl substituent at the ortho position to the aniline moiety. The ligand reacted with 0.5 equiv of CuCl2·2H2O in the presence of Et3N under air and provided the corresponding Cu(II)-bis(imonosemiquinone) complex (1). The complex upon oxidation by a stoichiometric amount of ferrocenium hexafluorophosphate (FcPF6) yielded the four-coordinate [Cu(II)-(imonosemiquinone)(iminoquinone)]PF6 complex (3), while the oxidation by an equivalent amount of CuCl2·2H2O produced the five-coordinate Cu(I)-bis(iminoquinone)Cl complex (2). Thus, a ligand-based oxidation followed by ligand-to-metal electron-transfer was realized for the latter oxidation process. Removal of the Cl- ion from complex 2 rendered the four-coordinate complex 4. The oxidation state of both Cu(I) and iminoquinone moieties remained unaltered upon the change in the coordination number. All the complexes were characterized by X-ray crystallography. Complexes 2, 3, and 4 were diamagnetic with an St = 0 ground state as evident by electron paramagnetic resonance (EPR) and 1H NMR measurements. The UV-vis-NIR spectra of all the complexes were dominated by charge-transfer transitions. Two oxidations and two reductions waves were noticed in the cyclic voltammogram (CV) of complex 1. Complex 2 and complex 3 underwent one oxidation and three reductions. Unlike complex 3, which experienced ligand-based oxidation, in complex 2 the oxidation was metal-centered [oxidation of Cu(I)-to-Cu(II)]. UV-vis-NIR spectral changes during the fixed-potential coulometric one-electron oxidation and thereafter EPR analysis consolidated the metal-based oxidation in complex 2. Complex 2 was air stable; however, it oxidized KO2 to oxygen molecule, and complex 1 was formed in due course as evident by UV-vis-NIR spectral changes and EPR measurements. Time dependent density functional theory calculations have been incorporated to assign the transitions that appeared in the UV-vis-NIR spectra of the complexes.

pH-Regulated anion transport activities of bis(iminourea) derivatives across the cell and vesicle membrane.

Recently, synthetic anion transporters have gained considerable attention because of their ability to disrupt cellular anion homeostasis and promote cell death. Herein, we report the development of bis(iminourea) derivatives as a new class of selective Cl- ion carrier. The bis(iminourea) derivatives were synthesized via a one-pot approach under mild reaction conditions. The presence of iminourea moieties suggests that the bis(iminourea) derivatives can be considered as unique guanidine mimics, indicating that the protonated framework could have much stronger anion recognition properties. The cooperative interactions of H+ and Cl- ions with these iminourea moieties results in the efficient transport of HCl across the lipid bilayer in an acidic environment. Under physiological conditions these compounds weakly transport Cl- ions via an antiport exchange mechanism. This pH-dependent gating/switching behavior (9-fold) within a narrow window could be due to the apparent pKa values (6.2-6.7) of the compounds within the lipid bilayer. The disruption of ionic homeostasis by the potent compounds was found to induce cell death.

Secondary amine salt catalyzed controlled activation of 2-deoxy sugar lactols towards alpha-selective dehydrative glycosylation.

A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. The catalytic generation of glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Brønsted-acidic, readily available secondary amine salts affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple iminium catalyzed activation of 2-deoxy hemi-acetals is a potential alternative to the existing cumbersome methods that need specialized handling. The mechanisms for this unique transformation and kinetic/thermodynamic effects have been discussed based on both experimental evidence and theoretical studies.

Energy decomposition analysis of cation-π, metal ion-lone pair, hydrogen bonded, charge-assisted hydrogen bonded, and π-π interactions.

This study probes the nature of noncovalent interactions, such as cation-π, metal ion-lone pair (M-LP), hydrogen bonding (HB), charge-assisted hydrogen bonding (CAHB), and π-π interactions, using energy decomposition schemes-density functional theory (DFT)-symmetry-adapted perturbation theory and reduced variational space. Among cation-π complexes, the polarization and electrostatic components are the major contributors to the interaction energy (IE) for metal ion-π complexes, while for onium ion-π complexes (NH4+, PH4+, OH3+, and SH3+) the dispersion component is prominent. For M-LP complexes, the electrostatic component contributes more to the IE except the dicationic metal ion complexes with H2 S and PH3 where the polarization component dominates. Although electrostatic component dominates for the HB and CAHB complexes, dispersion is predominant in π-π complexes.

Analogue and structure based approaches for modelling HIV-1 integrase inhibitors.

A set of 220 inhibitors belonging to different structure classes and having HIV-1 integrase activity were collected along with their experimental pIC50 values. Geometries of all the inhibitors were fully optimized using B3LYP/6-31 + G(d) level of theory. These ligands were docked against 4 different HIV-1 integrase receptors (PDB IDs: 4LH5, 5KRS, 3ZSQ and 3ZSV). 30 docked poses were generated for all 220 inhibitors and ligand interaction of the first docked pose and the docked pose with the highest score were analysed. Residue GLU170 of 4LH5 receptor shows the highest number of interactions followed by ALA169, GLN168, HIS171 and ASP167 residues. Hydrogen bonding and stacking are mainly responsible for the interactions of these inhibitors with the receptor. We performed Molecular Dynamics (MD) simulation to observe the root-mean-square deviation (RMSD), for measure the average change of displacement between the atoms for a particular frame with respect to a reference and The Root Mean Square Fluctuation (RMSF) for characterization of local changes along the protein chain of the docked complexes. Analogue based models were generated to predict the pIC50 values for integrase inhibitors using various types of descriptors such as constitutional, geometrical, topological, quantum chemical and docking based descriptors. The best models were selected on the basis of statistical parameters and were validated by training and test set division. A few new inhibitors were designed on the basis of structure activity relationship and their pIC50 values were predicted using the generated models. All the designed new inhibitors a very high potential and may be used as potent inhibitors of HIV integrase. These models may be useful for further design and development of new and potent HIV integrase inhibitors.Communicated by Ramaswamy H. Sarma.

Molecular dynamics investigation on a series of HIV protease inhibitors: assessing the performance of MM-PBSA and MM-GBSA approaches.

The binding free energies (ΔG(Bind)) obtained from molecular mechanics with Poisson-Boltzmann surface area (MM-PBSA) or molecular mechanics with Generalized Born surface area (MM-GBSA) calculations using molecular dynamics (MD) trajectories are the most popular procedures to measure the strength of interactions between a ligand and its receptor. Several attempts have been made to correlate the ΔG(Bind) and experimental IC(50) values in order to observe the relationship between binding strength of a ligand (with its receptor) and its inhibitory activity. The duration of MD simulations seems very important for getting acceptable correlation. Here, we are presenting a systematic study to estimate the reasonable MD simulation time for acceptable correlation between ΔG(Bind) and experimental IC(50) values. A comparison between MM-PBSA and MM-GBSA approaches is also presented at various time scales. MD simulations (10 ns) for 14 HIV protease inhibitors have been carried out by using the Amber program. MM-PBSA/GBSA based ΔG(Bind) have been calculated and correlated with experimental IC(50) values at different time scales (0-1 to 0-10 ns). This study clearly demonstrates that the MM-PBSA based ΔG(Bind) (ΔG(Bind)-PB) values provide very good correlation with experimental IC(50) values (quantitative and qualitative) when MD simulation is carried out for a longer time; however, MM-GBSA based ΔG(Bind) (ΔG(Bind)-GB) values show acceptable correlation for shorter time of simulation also. The accuracy of ΔG(Bind)-PB increases and ΔG(Bind)-GB remains almost constant with the increasing time of simulation.

Calculation of transition dipole moment in fluorescent proteins--towards efficient energy transfer.

Förster Resonance Energy Transfer (FRET) between fluorescent proteins (FPs) is widely used to construct fluorescent sensor proteins, to study intracellular protein-protein interactions and to monitor conformational changes in multidomain proteins. Although FRET depends strongly on the orientation of the transition dipole moments (TDMs) of the donor and acceptor fluorophores, this orientation dependence is currently not taken into account in FRET sensor design. Similarly, studies that use FRET to derive structural constrains typically assume a κ(2) of 2/3 or use the TDM of green fluorescent protein, as this is the only FP for which the TDM has been determined experimentally. Here we used time-dependent density functional theory (TD-DFT) methods to calculate the TDM for a comprehensive list of commonly used fluorescent proteins. The method was validated against higher levels of calculation. Validation with model compounds and the experimentally determined TDM of GFP shows that the TDM is mostly determined by the structure of the π-conjugated fluorophore and is insensitive to non-conjugated side chains or the protein surrounding. Our calculations not only provide TDM for most of the currently used FPs, but also suggest an empirical rule that can be used to obtain the TDMs for newly developed fluorescent proteins in the future.

Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate-binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.Communicated by Ramaswamy H. Sarma.

Comparison of computational methods to model DNA minor groove binders.

There has been a profound interest in designing small molecules that interact in sequence-selective fashion with DNA minor grooves. However, most in silico approaches have not been parametrized for DNA ligand interaction. In this regard, a systematic computational analysis of 57 available PDB structures of noncovalent DNA minor groove binders has been undertaken. The study starts with a rigorous benchmarking of GOLD, GLIDE, CDOCKER, and AUTODOCK docking protocols followed by developing QSSR models and finally molecular dynamics simulations. In GOLD and GLIDE, the orientation of the best score pose is closer to the lowest rmsd pose, and the deviation in the conformation of various poses is also smaller compared to other docking protocols. Efficient QSSR models were developed with constitutional, topological, and quantum chemical descriptors on the basis of B3LYP/6-31G* optimized geometries, and with this ΔT(m) values of 46 ligands were predicted. Molecular dynamics simulations of the 14 DNA-ligand complexes with Amber 8.0 show that the complexes are stable in aqueous conditions and do not undergo noticeable fluctuations during the 5 ns production run, with respect to their initial placement in the minor groove region.

Viability of clathrate hydrates as CO2 capturing agents: a theoretical study.

Capture and sequestration of green house gas CO(2) is a major challenge for scientists and identifying right materials for this purpose is a task of outstanding importance. Through reliable computational studies, we have demonstrated that the clathrate cages (5(12), 4(3)5(6)6(3), 5(12)6(2), 5(12)6(4), and 5(12)6(8)) have a great potential to store CO(2). All the considered clathrates and their CO(2) inclusion complexes are optimized at B3LYP/6-31G(d) level of theory. The impact of DFT-D, M05-2X, and MP2 functionals on interaction energy were tested using various basis sets. Although different functionals and basis sets show variation in absolute IE values, the trend is consistent and does not depend on the level of the calculations. Dispersion was found important for these complexes and DFT-D shows comparable IE values with MP2 functional. The optimum and maximum cage occupancy for all the considered cages were tested on the basis of quantum chemical calculations. The maximum cage occupancy for all five considered cages (5(12), 4(3)5(6)6(3), 5(12)6(2), 5(12)6(4), and 5(12)6(8)) is one, two, two, two, and seven CO(2) molecules, respectively, and the optimum cage occupancy is one, one, one, two, and five CO(2) molecules, respectively. Thus, 5(12)6(8) cages can host up to 7 CO(2) molecules, resulting in about 32 wt %, which makes them highly promising materials.

Selective Catalytic Synthesis of α-Alkylated Ketones and ß-Disubstituted Ketones via Acceptorless Dehydrogenative Cross-Coupling of Alcohols.

Herein, a phosphine-free pincer ruthenium(III) catalyzed ß-alkylation of secondary alcohols with primary alcohols to α-alkylated ketones and two different secondary alcohols to ß-branched ketones are reported. Notably, this transformation is environmentally benign and atom efficient with H2O and H2 gas as the only byproducts. The protocol is extended to gram-scale reaction and for functionalization of complex vitamin E and cholesterol derivatives.

Peptide-like and small-molecule inhibitors against Covid-19.

Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, more than 1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. Here, we utilized the in-silico approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compounds were screened from the CHEMBL database, ZINC database, FDA approved drugs and molecules under clinical trials. Our study is based on 6Y2F and 6W63 co-crystallized structures available in the protein data bank (PDB). Seven hundred compounds from ZINC/CHEMBL databases and fourteen hundred compounds from drug-bank were selected based on positive interactions with the reported binding site. All the selected compounds were subjected to standard-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed to screen the best compounds based on docking scores and binding energy values. Molecular dynamics (MD) simulations were carried out on four selected compounds from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened molecules and co-crystallized ligand. We screened 300 potential compounds from various databases, and 66 potential compounds from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened molecules from FDA approved drugs. The screened drugs and molecules may be helpful in fighting with SARS-CoV-2 after further studies.Communicated by Ramaswamy H. Sarma.

Can DFT methods correctly and efficiently predict the coordination number of copper(I) complexes? A case study.

The coordination number of various experimentally known Cu(I) compounds is studied using density functional theory. Various basis sets are tested, aiming to establish a reliable level for prediction of the coordination number of these and other Cu(I) complexes. It is found that most levels exhibit correct trends, namely, the bulkier ligands demonstrate larger preference for coordination of two ligands. Proper absolute values are obtained when dispersion corrections are also included in the calculations. It is concluded that the fairly small modified 6-31+G* basis set due to Pulay represents a good compromise between accuracy and efficiency, followed by Balabanov and Peterson's all-electron aug-cc-pVDZ basis set. The overall energy is decomposed into various components whose relative contribution to the overall tendency of forming a complex with a particular coordination is examined. It is shown that two opposing contributions play a major role: the interaction energy of the ligand being added and the deformation energy of the copper's coordination sphere prior to the ligand addition. The former being a stabilizing contribution, leads to higher coordination numbers while the later, a destabilizing contribution, is shown to favor lower coordination numbers.

Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents.

A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.

Selective and high yield transformation of glycerol to lactic acid using NNN pincer ruthenium catalysts.

The conversion of glycerol selectively to lactic acid has been accomplished in high yields (ca. 90%) by using a NNN pincer-Ru catalyst. DFT explains the role of the Ru-P bond and sterics in favoring the catalysis.

Synthesis of ß- and γ-lactam fused dihydropyrazinones from Ugi adducts via a sequential ring construction strategy.

A modular approach for the construction of ß- and γ-lactam fused dihydropyrazinones from the readily available Ugi adducts has been described. The sequential construction of rings through base-mediated cycloisomerization followed by acid-mediated cyclization yielded ß-lactam fused dihydropyrazinones. However, the Ugi-derived dihydropyrazinones afforded γ-lactam fused dihydropyrazinones under base-mediated cycloisomerization. The regioselectivity in the cycloisomerization reactions is explained on the basis of ring-strain. Substrate scope, limitations and mechanistic investigations through DFT-calculations have been explored.

Visible-Light-Mediated Ir(III)-Catalyzed Concomitant C3 Oxidation and C2 Amination of Indoles.

A visible-light-mediated concomitant C3 oxidation and C2 amination of indoles has been achieved at room temperature using an Ir (III) photocatalyst. This reaction proceeds without an isatin intermediate via the attack of a singlet oxygen at the C3 position followed by C2 amination leading to difunctionalization of indoles.