In Silico Design and Investigation of Novel Thiazetidine Derivatives as Potent Inhibitors of PrpR in Mycobacterium tuberculosis.

Tuberculosis is one of the most life-threatening acute infectious diseases diagnosed in humans. In the present investigation, a series of 16 new disubstituted 1,3-thiazetidines derivatives is designed, and investigated via various in silico methods for their potential as anti-tubercular agent by evaluating their ability to block the active site of PrpR transcription factor protein of Mycobacterium tuberculosis. The efficacy of the molecules was initially assessed with the help of AutoDock Vina algorithm. Further Glide module is used to redock the previously docked complexes. The binding energies and other physiochemical properties of the designed molecules were evaluated using the Prime-MM/GBSA and the QikProp module, respectively. The results of docking revealed the nature, site of interaction and the binding affinity between the proposed candidates and the active site of PrpR. Further the inhibitory effect of the scaffolds was predicted and evaluated employing a machine learning-based algorithm and was used accordingly. Further, the molecular dynamics simulation studies ascertained the binding characteristics of the unique 13, when analysed across a time frame of 100 ns with GROMACS software. The results show that the proposed 1,3-thiazetidine derivatives such as 10, 11, 13 and 14 could be potent and selective anti-tubercular agents as compared to the standard drug Pyrazinamide. Finally, this study concludes that designed thiazetidines can be employed as anti-tubercular agents. Undeniably, the results may guide the experimental biologists to develop safe and non-toxic drugs against tuberculosis by demanding further in vivo and in vitro analyses.

Insights on Chemical Crosslinking Strategies for Proteins.

Crosslinking of proteins has gained immense significance in the fabrication of biomaterials for various health care applications. Various novel chemical-based strategies are being continuously developed for intra-/inter-molecular crosslinking of proteins to create a network/matrix with desired mechanical/functional properties without imparting toxicity to the host system. Many materials that are used in biomedical and food packaging industries are prepared by chemical means of crosslinking the proteins, besides the physical or enzymatic means of crosslinking. Such chemical methods utilize the chemical compounds or crosslinkers available from natural sources or synthetically generated with the ability to form covalent/non-covalent bonds with proteins. Such linkages are possible with chemicals like carbodiimides/epoxides, while photo-induced novel chemical crosslinkers are also available. In this review, we have discussed different protein crosslinking strategies under chemical methods, along with the corresponding crosslinking reactions/conditions, material properties and significant applications.

In-silico molecular modelling, MM/GBSA binding free energy and molecular dynamics simulation study of novel pyrido fused imidazo[4,5-c]quinolines as potential anti-tumor agents.

With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

Computationally approached inhibition potential of Tinospora cordifolia towards COVID-19 targets.

The recent emergence of novel coronavirus (SARS-CoV-2) has been a major threat to human society, as the challenge of finding suitable drug or vaccine is not met till date. With increasing morbidity and mortality, the need for novel drug candidates is under great demand. The investigations are progressing towards COVID-19 therapeutics. Among the various strategies employed, the use of repurposed drugs is competing along with novel drug inventions. Based on the therapeutic significance, the chemical constituents from the extract of Tinospora cordifolia belonging to various classes like alkaloids, lignans, steroids and terpenoids are investigated as potential drug candidates for COVID-19. The inhibition potential of the proposed compounds against viral spike protein and human receptor ACE2 were evaluated by computational molecular modeling (Auto dock), along with their ADME/T properties. Prior to docking, the initial geometry of the compounds were optimized by Density functional theory (DFT) method employing B3LYP hybrid functional and 6-311 + + G (d,p) basis set. The results of molecular docking and ADME/T studies have revealed 6 constituents as potential drug candidates that can inhibit the binding of SARS-CoV-2 spike protein with the human receptor ACE2 protein. The narrowed down list of constituents from Tinospora cordifolia paved way for further tuning their ability to inhibit COVID-19 by modifying the chemical structures and by employing computational geometry optimization and docking methods. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13337-021-00666-7.

Light emitting probes - approaches for interdisciplinary applications.

Though the field of fluorescent sensors has been known for more than 150 years, tremendous developments were made in the past two decades with the emergence of fluorescence-based optical sensors that are now inevitable tools for sensing a variety of biological, chemical and environmental analytes. These probes are simple, highly sensitive, selective and specific towards detection. There are several unique mechanisms adopted by these probes towards sensing analytes. This tutorial review introduces various fluorescent probes that are being employed in the development of chemo- and bio-sensors for the detection of various charged and neutral species, including biomacromolecules like proteins and nucleic acids. This review mainly focuses on basic principles involved in the design of probes with different sensing methods like self-immolation, peptide beacon, FRET, photo-induced electron/charge transfer, etc. The complexity observed in biological systems with interference from numerous other analytes and the necessity to use multiple probes was overcome by using multiple responsive probes. Herein we have discussed the design and sensing mechanism of various probes that find applications in physical, chemical and biological sciences, diagnostics and therapeutics.

An efficient single pot DNA recombination method for protein library generation.

A simple single pot method was developed to generate a library of protein hybrids/chimeras from unrelated parents. This method allows unbiased facile DNA shuffling based recombination between the parents with the introduction of type IIB restriction enzyme, BsaXI, at multiple distinct crossover sites. To assess this methodology, B1 immunoglobulin domain of protein G and top7 were recombined at four sites, yielding 25 (32) possible hybrid proteins. Tandem colony multiplex PCR based screening was followed to screen the hybrid clones and, sequencing analysis confirmed seven hybrid clones with no sequence bias.

Environment dependent photophysical and fluorescence turn-off sensing properties of Fe(iii) by substituted phenyl isochromenopyrrol-5-ones.

Analogues of isochromenopyrrolone were synthesized using Montomorillonite K10 as a catalyst and characterized. The electronic structure and geometry of all the synthesized compounds were investigated experimentally by UV-visible absorption and fluorescence spectroscopy. A negligible shift was observed in the absorption spectrum while a large red shift was observed in the fluorescence spectrum upon changing from non-polar to polar solvents. The experimental results were compared with those from density functional theory calculations. The observed photophysical properties were induced from the solvent environment. Except for chlorosubstituition, other functional groups like methyl, dimethyl, diethyl or methoxy, did not influence the electronic properties of the molecules significantly. The experimental results were in good agreement with the theoretical interpretations. Moreover, these isochromenopyrrolones possess excellent sensing ability for Fe(iii) ions via the fluorescence turn-off mechanism with a detection limit of ∼10-6 M and an association constant of ∼103 M-1. It is proposed that these molecules can find their use in environment sensing applications.

Efficient Access to Imidazo[1,2- a]pyridines/pyrazines/pyrimidines via Catalyst-Free Annulation Reaction under Microwave Irradiation in Green Solvent.

An expeditious catalyst-free heteroannulation reaction for imidazo[1,2- a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using H2O-IPA as the reaction medium, various substituted 2-aminopyridines/pyrazines/pyrimidines underwent annulation reaction with α-bromoketones under microwave irradiation to provide the corresponding imidazo[1,2- a]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic methodology appears to be very simple and superior to the already reported procedures with the high abundance of commercial reagents and great ability in expanding the molecular diversity. The present synthetic sequence is visualized as an environmentally benign process which allows the introduction of three points of structural diversity to expand chemical space with excellent purity and yields. The anti-inflammatory and antimicrobial activities of the derivatives were evaluated. Screening results uncovered three derivatives with strong inhibition of albumin denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive bioassay results implied that the library of potential anti-inflammatory agents could be rapidly prepared in an ecofriendly manner, and provided new insights into drug discovery for medicinal chemists.