Molecular Docking Studies of Dihydropyridazin-3(2H)-one Derivatives as Anticonvulsant Agents

Molecular docking is the identification of ligand’s correct binding geometry i.e. pose in the binding site and estimation of its binding affinity for rational design of drug molecule. The current study endeavored the high throughput in silico screening of 56 derivatives of dihydropyridazin-3(2H)-one docked with human cytosolic branched chain amino transferase using PyRx-virtual screening tool. Out of 56 compounds, almost all the test compounds showed very good binding affinity score. Gabapentin was used as standard drug which shows binding affinity of -6.2. On the basis of H-bond interactions, compounds 3, 9, 11, 25, 26, 31, 34, 39, 47, 48, 51, 54, 56 were found to be potent outcome for anticonvulsant activity. Compounds 11, 25, 39, 56 showed excellent H-bond interactions with protein active site, Among which compound 11 showed the outstanding interactions with acceptable bond length 2.34, 2.57, 2.62, 3.03 Å.

Using Enzymes to Tame Nitrogen-Centered Radicals for Enantioselective Hydroamination

The construction of C–N bonds is essential for the preparation of numerous molecules critical to modern society1,2. Nature has evolved enzymes to facilitate these transformations using nucleophilic and nitrene transfer mechanisms3,4. However, neither natural nor engineered enzymes are known to generate and control nitrogen-centered radicals, which serve as valuable species for C–N bond formation. Herein, we describe a platform for generating nitrogen-centered radicals within protein active sites, thus enabling asymmetric hydroamination reactions. Using flavin- dependent ‘ene’-reductases with an exogenous photoredox catalyst, amidyl radicals are generated selectively within the protein active site. Empowered by directed evolution, these enzymes are engineered to catalyze 5-exo, 6-endo, 7-endo, 8-endo, and intermolecular hydroamination reactions with high levels of enantioselectivity. Mechanistic studies suggest that radical initiation occurs via an enzyme-gated mechanism, where the protein thermodynamically activates the substrate for reduction by the photocatalyst. Molecular dynamics studies suggest that the enzymes bind substrates using non-canonical binding interactions, which may serve as a handle to further manipulate reactivity. This approach demonstrates the versatility of these enzymes for controlling the reactivity of high-energy radical intermediates and highlight the opportunity for synergistic catalyst strategies to unlock new enzymatic functions.

Molecular docking studies of dihydropyridazin-3(2H)-one derivatives as Antifungal, antibacterial and anti-helmintic agents

Molecular docking is the identification of ligand’s correct binding geometry i.e pose in the binding site and estimation of its binding affinity for the rational design of drug molecule. The current study endeavored the high throughput insilico screening of 24 compounds docked with their respective protein using PyRx-Virtual Screening Tool software. Out of 24 compounds, almost all test compounds showed a very good binding affinity score. Fluconazole was used as a standard drug in case of Antifungal, Ciprofloxacin in case of Antibacterial, and Albendazole in case of Antihelmintics. More negative is the binding free energy score, more favorable is the pose for binding to protein active site. Based on H-bond interactions of these 24 compounds, Compounds 3a5, 3c3, 3d5, 3d6 were found to be the similar outcome for antifungal activity as fluconazole, Compound3a1 for antibacterial, and Compounds 3b5, 3d6 for the antihelmintic agent. Furthermore, the affinity of any small ligand molecules can be considered as an extraordinary tool in the field of drug design and offer imminent in future examination to build up potent antimicrobial agents.

Synthesis of Novel Halogenated Heterocyclic compounds and their uses as Target SARS-CoV-2 main Protease (Mpro) and Potential Anti-Covid-19

Since the first appearance of the coronavirus disease-2019 (COVID-19) in Wuhan, China, in December 2019, it has been spreading globally with devastating ramifications. The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that are capable of targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). The latter plays a fundamental role in mediating viral replication and transcription, rendering it an attractive drug target. In this study, twenty six novel halogenated, heterocyclic compounds, which can inhibit Mpro, were tested by molecular docking combined with molecular dynamics simulation. Three compounds showed the highest binding affinity to the protein active site and their binding modes coincide with that of Nelfinavir. The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the virallife cycle. In times of dire need for anti-COVID-19 treatment, this study lays the groundwork for further experimental research to investigate the efficacy and potential medical uses of these compounds to treat COVID-19. Novel compounds including fused thiophene, pyrimidine and pyran derivatives were tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti covid-19 target molecules.

In silico study of thymohydroquinone interaction with blood–brain barrier disrupting proteins

Aim: To evaluate the inhibitory interaction of thymohydroquinone against blood–brain barrier (BBB)-associated neuropsychiatric and neurodegenerative disorders. Materials & methods: An elaborated in silico study was designed to evaluate the interaction of thymohydroquinone with BBB-disrupting proteins and to highlight its pharmacokinetic and safety attributes. Results: Thymohydroquinone demonstrated stable interaction with BBB-disrupting protein active site with Ki (inhibition constant) ranges of (2.71 mM–736.15 μM), binding energy (-4.3 to 5.6 Kcal/mol), ligand efficiency (-0.36 to 0.42 Kcal/mol) and root mean square deviation value of (0.80–2.59 Å). Conclusion: Further pharmacokinetic analysis revealed that thymohydroquinone is BBB and central nervous system (CNS) permeant with high acute toxicity and could be a candidate drug for the treatment of these neurological conditions.

Quaternary Charge-Transfer Complex Enables Photoenzymatic In-termolecular Hydroalkylation of Olefins

Intermolecular C–C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent ‘ene’reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, 𝛼-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.

Quaternary Charge-Transfer Complex Enables Photoenzymatic In-termolecular Hydroalkylation of Olefins

Intermolecular C–C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent ‘ene’reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, 𝛼-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.

Bioluminescent Properties of Semi-Synthetic Obelin and Aequorin Activated by Coelenterazine Analogues with Modifications of C-2, C-6, and C-8 Substituents

Ca2+-regulated photoproteins responsible for bioluminescence of a variety of marine organisms are single-chain globular proteins within the inner cavity of which the oxygenated coelenterazine, 2-hydroperoxycoelenterazine, is tightly bound. Alongside with native coelenterazine, photoproteins can also use its synthetic analogues as substrates to produce flash-type bioluminescence. However, information on the effect of modifications of various groups of coelenterazine and amino acid environment of the protein active site on the bioluminescent properties of the corresponding semi-synthetic photoproteins is fragmentary and often controversial. In this paper, we investigated the specific bioluminescence activity, light emission spectra, stopped-flow kinetics and sensitivity to calcium of the semi-synthetic aequorins and obelins activated by novel coelenterazine analogues and the recently reported coelenterazine derivatives. Several semi-synthetic photoproteins activated by the studied coelenterazine analogues displayed sufficient bioluminescence activities accompanied by various changes in the spectral and kinetic properties as well as in calcium sensitivity. The poor activity of certain semi-synthetic photoproteins might be attributed to instability of some coelenterazine analogues in solution and low efficiency of 2-hydroperoxy adduct formation. In most cases, semi-synthetic obelins and aequorins displayed different properties upon being activated by the same coelenterazine analogue. The results indicated that the OH-group at the C-6 phenyl ring of coelenterazine is important for the photoprotein bioluminescence and that the hydrogen-bond network around the substituent in position 6 of the imidazopyrazinone core could be the reason of different bioluminescence activities of aequorin and obelin with certain coelenterazine analogues.