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.

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.

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.

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.

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.

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.

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.

Trisulfides over disulfides: highly selective synthetic strategies, anti-proliferative activities and sustained H2S release profiles.

Temperature- and solvent-induced selective synthesis of trisulfides and disulfides is demonstrated. A remarkable selectivity was achieved using Na2S as a sulfur-transfer agent under mild, greener, catalyst-free and additive-free conditions. This study reveals trisulfides as a better model than disulfides in general for a sustained release of H2S and potent anti-cancer activities.

Stereospecific Assembly of Fused Imidazolidines via Tandem Ring Opening/Oxidative Amination of Aziridines with Cyclic Secondary Amines Using Photoredox Catalysis.

Sustainable assembly of imidazolidines is accomplished via a sequential stereospecific ring opening and C-H amination using aziridines with secondary cyclic amines under visible light mediated indazoloquinoline photoredox catalysis at ambient conditions. Optically active aziridines are coupled with high enantiomeric purities. The computational studies provide insights on the redox properties of the catalysts as well as a profile of the reaction.

Converting waste Allium sativum peel to nitrogen and sulphur co-doped photoluminescence carbon dots for solar conversion, cell labeling, and photobleaching diligences: A path from discarded waste to value-added products.

Proper waste utilization in order to promote value added product is a promising scientific practice in recent era. Inspiring from the recurring trend, we propose a single step oxidative pyrolysis derived fluorescent carbon dots (C-dots) from Allium sativum peel, which is a natural, nontoxic, and waste raw material. Because of its excellent optical properties, and photostability this C-dots have been used in versatile area of applications. Due to its immediate water dispersing character, C-dots reinforced Poly(acrylic acid) (PAA) films revealed improvement in uniaxial stretching behavior and can be used as transparent sunlight conversion film. The nanocomposite film has been tested against rigorous simulated sunlight which proved almost identical sunlight conversion behavior with no photo-bleachable character which is definitely added an extra quality of transparent polymer films. Moreover, the C-dots dispersion has been used as in vitro biomarker for living cells owing to its ease in solubility, biocompatibility, non-cytotoxicity and bright fluorescence even in subcutaneous environment. For this case, adipose derived mesenchymal stem cells (ADMSCs) have been chosen and injected to rabbit ear skin to perform two-photon imaging experiment. The present work opens a new avenue towards the large-scale synthesis of bio-waste based fluorescent C-dots, paving the way for their versatile applications.

tert-Butyl Nitrite Mediated Synthesis of 1,2,4-Oxadiazol-5(4 H)-ones from Terminal Aryl Alkenes.

tert-Butyl nitrite (TBN) mediated synthesis of 3-aryl-1,2,4-oxadiazol-5(4 H)-ones has been accomplished using terminal aryl alkenes via a biradical reaction intermediate. Three consecutive sp2 C-H bond functionalizations of styrenes afforded 3-phenyl-1,2,4-oxadiazol-5(4 H)-ones via the formation of new C═N, C═O, C-O, and two C-N bonds. Both of the N atoms originate from TBN, while the carbonyl oxygen is from the water (moisture) the other oxygen from the N═O part of the TBN.

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.

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.

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.

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.

One- and Two-Photon Uncaging: Carbazole Fused o-Hydroxycinnamate Platform for Dual Release of Alcohols (Same or Different) with Real-Time Monitoring.

A one- and two-photon activated photoremovable protecting group (PRPG) was designed based on a carbazole fused o-hydroxycinnamate platform for the dual (same or different) release of alcohols. The mechanism for the dual release proceeds through a stepwise pathway and also monitors the first and second photorelease in real time by an increase in fluorescence intensity and color change, respectively. Further, its application in staining live neurons and ex vivo imaging with two-photon excitation is shown.

Metal-Free Sequential C(sp2)-H/OH and C(sp3)-H Aminations of Nitrosoarenes and N-Heterocycles to Ring-Fused Imidazoles.

Hydrogen bond assisted ortho-selective C(sp2)-H amination of nitrosoarenes and subsequent α-C(sp3)-H functionalization of aliphatic amines is achieved under metal-free conditions. The annulation of nitrosoarenes and 2-hydroxy-C-nitroso compounds with N-heterocycles provides a facile excess to a wide range of biologically relevant ring-fused benzimidazoles and structurally novel polycyclic imidazoles, respectively. Nucleophilic aromatic hydrogen substitution (SNArH) was found to be preferred over classical SNAr reaction during the C(sp2)-H amination of halogenated nitrosoarenes.

A web server for analysis, comparison and prediction of protein ligand binding sites.

BACKGROUND: One of the major challenges in the field of system biology is to understand the interaction between a wide range of proteins and ligands. In the past, methods have been developed for predicting binding sites in a protein for a limited number of ligands. RESULTS: In order to address this problem, we developed a web server named 'LPIcom' to facilitate users in understanding protein-ligand interaction. Analysis, comparison and prediction modules are available in the "LPIcom' server to predict protein-ligand interacting residues for 824 ligands. Each ligand must have at least 30 protein binding sites in PDB. Analysis module of the server can identify residues preferred in interaction and binding motif for a given ligand; for example residues glycine, lysine and arginine are preferred in ATP binding sites. Comparison module of the server allows comparing protein-binding sites of multiple ligands to understand the similarity between ligands based on their binding site. This module indicates that ATP, ADP and GTP ligands are in the same cluster and thus their binding sites or interacting residues exhibit a high level of similarity. Propensity-based prediction module has been developed for predicting ligand-interacting residues in a protein for more than 800 ligands. In addition, a number of web-based tools have been integrated to facilitate users in creating web logo and two-sample between ligand interacting and non-interacting residues. CONCLUSIONS: In summary, this manuscript presents a web-server for analysis of ligand interacting residue. This server is available for public use from URL http://crdd.osdd.net/raghava/lpicom .