N'-(3,4-dimethoxybenzylidene)-4-methylbenzenesulfonohydrazide derivatives: Synthesis, Quantum Chemical Method, in silico ADMET, Molecular docking and Molecular dynamic simulations

A new N'-(3,4-dimethoxybenzylidene)-4-methylbenzenesulfonohydrazide derivatives were prepared from a condensation reaction between 4-methylbenzenesulfonohydrazide and 3,4-dimethoxybenzaldehyde. The structure of DMSH was elucidated using various spectral techniques including FT-IR, 1H-NMR and 13C-NMR. The structure of DMSH bond parameters also confirmed by single crystal XRD analysis of related derivatives and optimized bond parameters are calculated by density functional theory (DFT) method at B3LYP/6-311G (d, p) level of theory. The optimized geometrical parameters obtained by DFT calculation are in good agreement with single crystal XRD data. The experimentally observed FT-IR bands were assigned to different normal modes of the molecule. The results show a good agreement with each other when these computed bond parameters are compared to XRD values of related compounds. The stability, chemical reactivity and charge transfer within the molecule was explained by frontier molecular orbital calculations. Atomic charges on the various atoms of DMSH obtained by Mulliken population analysis. Potential reactive sites of the DMSH compound have been identified by MEP which is mapped to the electron density surfaces. The reported molecule is used as a potential NLO material since it has a high μβ0 value. The theoretical UV-vis spectrum of the compound is used to study the visible absorption maxima (λ max). The molecular docking mechanism between DMSH ligand and COVID-19/6WCF and COVID-19/6Y84 receptors were studied to investigate the binding modes of this compound at the active sites. Molecular docking outcomes have shown that the DMSH molecule can be considered as a potential agent against COVID-19/6WCF-6Y84 receptors. In addition, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness qualities and ADME/T analysis was carried out to examine the drug properties of the synthesized compound. Molecular dynamics simulation was performed for COVID-19 main protease (Mpro: 6WCF/6Y84) to understand the elements governing the inhibitory effect and the stability of interaction under dynamic conditions. The resultant complex structures were subjected to 100 ns simulation run to estimate their binding stabilities using GROMACS. The molecular dynamics simulation studies provided essential evidence that the systems were stable during the progression of 100 ns simulation run.

Ultrasound assisted regioselective synthesis of novel adamantyl-pyrazolo[1,5-a]pyrimidines in aqueous media and molecular docking and drug likeness studies

Multi-step synthesis of adamantyl-pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation has been described adopting the technique of molecular hybridization, whereby two core bioactive units- adamantanamine and pyrazolo[1,5-a]pyrimidine templates have been brought together into a new chemical entity. Ultrasound irradiation of N-(adamantan-1-yl)-3-amino-1H-pyrazole-4-carboxamide with formylated active proton compounds yields the desired hybrids in good to excellent yields. The N-(adamantan-1-yl)-3-amino pyrazolo[1,5-a]pyrimidine carboxamide derivatives were successfully identified with the help of spectral and analytical data. X-ray crystallography of ethyl 3-(adamantan-1-ylcarbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (14c) unambiguously confirmed the formation of the desired hybrid. The results and the findings of the docking scores indicate that the active ligands 7a and 11b exhibited highest binding energies with a score of –7.33 Kcal/mol and – 8.73 Kcal/mol, respectively. The inhibition constant (KI) for ligands 7a and 11b were found to be 4.24 µM and 396.32 µM, respectively which are comparatively lower than the control favipiravir thereby conforming to the drug-likeness prediction. These compounds as such become favorable for screening as drug candidates compared to the control favipiravir with lower binding energy, lower lipophilicity range and very high KI constant. The active ligands have promising functions to inhibit and interfere with the replication and maturation of Chymotrypsin-like protease (3CLpro) of SARS-Coronavirus 2. The lower KI, high binding energy and drug-likeness efficiency of the compounds can be further developed into a potent drug molecule against the uncontrollable SARS-COV-2.

Computational investigation of Arbutus serratifolia Salisb molecules as new potential SARS-CoV-2 inhibitors

The outbreak of the current pandemic and the evolution of virus resistance against standard drugs led to the emergency of new and potent antiviral agents. Owing to its crucial role in viral replication, the protease enzyme is taken into survey to be a promising target for antiviral drug therapy using computational methods. In order to bring this important class of natural products in the limelight of research for prospective application as chemotherapeutic agents, the anti-SARS-CoV-2 activity of some bioactive molecules obtained from Arbutus serratifolia Salisb which is an Algerian medicinal plant, was investigated using in-silico methods. The molecular docking was performed by AutoDock Vina and UCSF Chimera, as well as ADMET and drug-likeness properties of these molecules were calculated using preADMET web-based application and the Swiss ADME server respectively. The phytochemicals (from Pr(1) to Pr(12)) were tested for their pharmacokinetic properties and docked into the main protease binding site on (PDB ID: 6Y84) in order to find a promising antiviral ligand. All tested molecules induced binding affinities into the binding pocket of (PDB ID: 6Y84) with energy scores ranging from moderate to better (from -6.4 to -8.00 kcal/mol). It is worthy to note that both Pr(2): (1S,5R,6S,8S,9S)-6,8-Dihydroxy-8-methyl-1,5,6,7,8,9-hexahydrocyclopenta [c] pyran-1-yl-β-D-glucopyranoside and Pr(7): ((1S,5S,6S,9S)-1-(β-D-Glucopyranosyloxy)-14-oxo-1,5,6,9-tetrahydro-1H-2,15-dioxacyclopenta [cd] inden-8-yl) methyl acetate, were found to be the best inhibitors with binding affinities (-7.7 kcal/mol and -8.0 kcal/mol), respectively, by virtue of the fact that all these tested molecules exhibited good binding affinities compared with those of Ritonavir and Nirmatrelvir (-1.73 and -1.93 kcal/mol), respectively, which are used as standard antiviral drugs to prevent viral growth. The amino acids: His-163;Glu-166;Arg-188;Thr-190 and Gln-192 represent the key residues of the interaction of SARS-CoV-2 main protease with Pr(7). Furthermore, the results of pharmacodynamic and pharmacokinetic investigations revealed that Pr(6), Pr(8) and Pr(9) uphold the drug-likeness criteria and more particularly, these substances can be absorbed by the human intestine. In addition, all these molecules were shown to be neither hepatotoxic nor significantly noxious to human organism. These natural products are therefore promising inhibitor candidates of viral main protease. However, further in-vitro, in-vivo and even clinical assays are required to probe their functional mechanisms and then to assess their antiviral potency against COVID-19. © 2023 Walter de Gruyter GmbH, Berlin/Boston 2023.

In-silico studies on wild orange (Citrus macroptera Mont.) compounds against COVID-19 pro-inflammation targets.

One-fifth of COVID-19 patients suffer a severe course of COVID-19 (SARS-CoV-2) infection; however, the specific causes remain unclear. Despite numerous papers that have been flooded in different scientific journals clear clinical picture of COVID-19 aftermath persists to remain fuzzy. The survivors of severe COVID-19infection having defeated the virus are just the starting of an uncharted recovery path. Currently, there is no drug available that is safe to consume to combat this pandemic. However, researchers still struggling to find specific therapeutic solutions. The present study employed an in silico approach to assessing the inhibitory potential of the phytochemicals obtained from GC-MS analysis of Citrus macroptera against inflammatory proteins like COX-2, NMDAR and VCAM-1 which remains in a hyperactive state even after a patient is fully cured of this deadly mRNA virus. An extensive molecular docking investigation of the phyto-compounds at the active binding pockets of the inflammatory proteins revealed the promising inhibitory potential of the phytochemicals. Reasonable physicochemical attributes of the compounds following Lipinski's rule of five, VEBER and PAINS analysis further established them as potential therapeutic candidates against aforesaid inflammatory proteins. MM-GBSA binding free energy estimation revealed that Limonene was the most promising candidate displaying the highest binding efficacy with the concerned VCAM-1 protein included in the present analysis. An interesting finding is the phytochemicals exhibited better binding energy scores with the concerned COX-2, VCAM-1 and NMDA receptor proteins than the conventional drugs that are specifically targeted against them. Our in silico results suggest that all the natural phyto-compounds derived from C. macroptera could be employed in Post covid inflammation complexities after appropriate pre-clinical and clinical trials for further scientific validation.Communicated by Ramaswamy H. Sarma.

Crystal Growth, Structural, Vibrational, Effects of Hydrogen Bonding(C-H…O and C-H…N), Chemical Reactivity, Antimicrobial Activity, Inhibitory Effects and Molecular Dynamic Simulation of 4-Methoxy-N-(Nitrobenzylidene)-Aniline

The present study aims to provide deeper knowledge about the structural, vibrational, chemical, antimicrobial activity, molecular dynamic simulation and drug likeness of synthesized compound 4-Methoxy-N-(nitrobenzylidene)-aniline. The FT-IR and FT-Raman spectra of 4-Methoxy-N-(nitrobenzylidene)-aniline have been recorded in the powder form in the region 4000–500 cm−1 and 3500–50 cm−1. The vibrational analysis were carried out with the help of normal coordinate analysis (NCA). The molecular geometry, hydrogen bonding interaction and vibrational frequencies have been calculated using the density functional method (DFT/B3LYP) with 6-311 G (D) basis set. The natural bond orbital (NBO), atoms in molecule (AIM), and Hirshfeld surface analysis and RDG were applied to evaluate the relative strength of hydrogen bond interactions and represent their effect on the stabilities of molecular arrangements. Related molecules were compared by computation in order to understand the effect of non-bonded interactions (i.e. intermolecular and intramolecular hydrogen bonding). The HOMO and LUMO analysis was used to determine the charge transfer within the molecule. Furthermore, the in vitro antimicrobial study was carried out for the title compound against Aspergillus niger and Staphylococcus aureus. The antimicrobial activity was confirmed on the compounds with molecular docking (A.niger, S.aureus, Homosapians, Sars-Cov-19 and anticancer) studies and molecular dynamic simulation. The non-linear optical (NLO) properties were also analyzed for the molecules.

Bioprospecting phytochemicals of Rosmarinus officinalis L. for targeting SARS-CoV-2 main protease (Mpro): a computational study.

CONTEXT: The persistent spread of highly contagious COVID-19 disease is one of the deadliest occurrences in the history of mankind. Despite the distribution of numerous efficacious vaccines and their extensive usage, the perpetual effectiveness of immunization is being catechized. Therefore, discovering an alternative therapy to control and prevent COVID-19 infections has become a top priority. The main protease (Mpro) plays a key role in viral replication, making it an intriguing pharmacological target for SARS-CoV-2. METHODS: In this context, virtual screening of thirteen bioactive polyphenols and terpenoids of Rosmarinus officinalis L. was performed using several computational modules including molecular docking, ADMET, drug-likeness characteristics, and molecular dynamic simulation to predict the potential inhibitors against SARS-CoV-2 Mpro (PDB: 6LU7). The results suggest that apigenin, betulinic acid, luteolin, carnosol, and rosmarinic acid may emerge as potential inhibitors of SARS-CoV-2 with acceptable drug-likeness, pharmacokinetics, ADMET characteristics, and binding interactions comparable with remdesivir and favipiravir. These findings imply that some of the active components of Rosmarinus officinalis L. can serve as an effective antiviral source for the development of therapeutics for SARS-CoV-2 infection.

Design, synthesis, and computational studies of novel imidazo[1,2-a]pyrimidine derivatives as potential dual inhibitors of hACE2 and spike protein for blocking SARS-CoV-2 cell entry.

In the present work, a new series of imidazo[1,2-a]pyrimidine Schiff base derivatives have been obtained using an easy and conventional synthetic route. The synthesized compounds were spectroscopically characterized using 1H, 13C NMR, LC-MS(ESI), and FT-IR techniques. Green metric calculations indicate adherence to several green chemistry principles. The energy of Frontier Molecular Orbitals (FMO), Molecular Electrostatic Potential (MEP), Quantum Theory of Atoms in Molecules (QTAIM), and Reduced Density Gradient (RDG) were determined by the Density Functional Theory (DFT) method at B3LYP/6-31 G (d, p) as the basis set. Moreover, molecular docking studies targeting the human ACE2 and the spike, key entrance proteins of the severe acute respiratory syndrome coronavirus-2 were carried out along with hACE2 natural ligand Angiotensin II, the MLN-4760 inhibitor as well as the Cannabidiolic Acid CBDA which has been demonstrated to bind to the spike protein and block cell entry. The molecular modeling results showed auspicious results in terms of binding affinity as the top-scoring compound exhibited a remarkable affinity (-9.1 and -7.3 kcal/mol) to the ACE2 and spike protein respectively compared to CBDA (-5.7 kcal/mol), the MLN-4760 inhibitor (-7.3 kcal/mol), and angiotensin II (-9.2 kcal/mol). These findings suggest that the synthesized compounds may potentially act as effective entrance inhibitors, preventing the SARS-CoV-2 infection of human cells. Furthermore, in silico, ADMET, and drug-likeness prediction expressed promising drug-like characteristics.

In silico screening of Pueraria tuberosa (PTY-2) for targeting COVID-19 by countering dual targets Mpro and TMPRSS2.

COVID-19 pandemic was started in Wuhan city of China in December 2019; immensely affected global population. Herein, an effort was made to identify potential inhibitors from active phytochemicals of Pueraria tuberosa (PTY-2) via molecular docking study. Our study showed five potential inhibitors (Robinin, Genistin, Daidzin, Hydroxytuberosone, Tuberostan) against Mpro and five inhibitors (Robinin, Anhydrotuberosin, Daidzin, Hydroxytuberosone, Stigmasterol) against TMPRSS2. Out of these, Robinin, Daidzin and Hydroxytuberosone were common inhibitors for Mpro and TMPRSS2. Among these, Robinin showed the highest binding affinity, therefore, tested for MD simulation runs and found stable. ADMET analysis revealed the best-docked compounds are safe and follow the Lipinski Rule of Five. Thus, it could be suggested that phytochemicals of PTY-2 could serve as potential inhibitors for COVID-19 targets.Communicated by Ramaswamy H. Sarma.

The novel tetrahydropyrimidine derivative as inhibitor of SARS CoV-2: synthesis, modeling and molecular docking analysis.

N-(1,3-Benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine was synthesized and characterized by elemental analysis, FT-IR, NMR and X-ray single crystal diffraction. The compound structure belongs to the triclinic system with the P-1 space group with unit cell parameters a = 11.9290(4), b = 13.2547(4) and c = 15.3904(5) Å. Hirhsfeld surface analysis is performed to revealintermolecular interactions with these interactions. The molecular structure, vibrational spectroscopic data and HOMOs and LUMOs analyses were calculated by using the DFT/B3LYP method with the 6-311 + G(d,p)) basis set. Some of pharmacokinetic parameters and drug-likeness properties of the compound were also performed. Besides these, the present work is a searching to test N-(1,3-benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine as an inhibitor for the SARS-CoV-2. For this aim, the molecular docking analysis of the synthesized compound was applied along with Favipiravir. Besides the docking results, ADMET properties of the compound were also calculated.Communicated by Ramaswamy H. Sarma.

In silico bioprospecting of antiviral compounds from marine fungi and mushroom for rapid development of nutraceuticals against SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) affects human respiratory function that causes COVID-19 disease. COVID-19 has spread rapidly all over the world and became a pandemic within no time. Therefore, it is the need of hour to screen potential lead candidates from natural resources like edible mushrooms and marine fungi. These natural resources are very less explored till now and known to be the source for many medicinal compounds with several health benefits. These medicinal compounds can be easily exploited for the faster development of nutraceuticals for controlling SARS-CoV-2 infections. Our Insilico research suggests, bioactive compounds originating from mushroom and marine fungi shows strong potential to interact with ACE2 receptor or main protease of SARS-CoV-2, showing the inhibition activity towards the enzymatic protease. We performed a series of Insilico studies for the validation of our results, which includes Molecular docking, drug likeness property investigation by Swiss ADME tools, MD simulation, and thermodynamically stable free binding energy calculation. Overall, these results suggest that Ganodermadiol and Heliantriol F bioactive compounds originating from edible mushroom has strong potential to be developed as low-cost nutraceutical against SARS-CoV-2 viral infection. The drug candidate isolated from marine fungi and edible mushroom are highly unexplored for the development of potential alternative drug against SARS-CoV-2 virus with minimum side effects. Though our in silico studies of these compounds are showing a promising results against SARS-CoV-2 main protease and ACE2 receptor binding domain, the effectiveness of these bioactive compounds should be further validated by proper clinical trials.Communicated by Ramaswamy H. Sarma.

Identification of Pyrazole Derivatives of Usnic Acid as Novel Inhibitor of SARS-CoV-2 Main Protease Through Virtual Screening Approaches.

The infection produced by the SARS-CoV-2 virus remains a significant health crisis worldwide. The lack of specific medications for COVID-19 necessitates a concerted effort to find the much-desired therapies for this condition. The main protease (Mpro) of SARS-CoV-2 is a promising target, vital for virus replication and transcription. In this study, fifty pyrazole derivatives were tested for their pharmacokinetics and drugability, resulting in eight hit compounds. Subsequent molecular docking simulations on SARS-CoV-2 main protease afforded two lead compounds with strong affinity at the active site. Additionally, the molecular dynamics (MD) simulations of lead compounds (17 and 39), along with binding free energy calculations, were accomplished to validate the stability of the docked complexes and the binding poses achieved in docking experiments. Based on these findings, compound 17 and 39, with their favorable projected pharmacokinetics and pharmacological characteristics, are the proposed potential antiviral candidates which require further investigation to be used as anti-SARS-CoV-2 medication.

One-pot synthesis, NMR, quantum chemical approach, molecular docking studies, drug-likeness and in-silico ADMET prediction of novel 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(furan-2-yl)-4,5-diphenyl-1H-imidazole derivatives.

A novel drug to treat SARS-CoV-2 infections and hydroxyl chloroquine analogue, 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(furan-2-yl)-4,5-diphenyl-1H-imidazole (DDFDI) compound has been synthesized in one pot reaction. The novel compound DDFDI had been characterized by FT-IR, 1H-NMR and 13C-NMR spectral techniques. The geometrical structure was optimized by density functional theory (DFT) method at B3LYP/6-31G (d, p) as the basis set. The smaller energy value provides the higher reactivity of DDFDI compound than hydroxyl chloroquine and was corrected by high electrophilic and low nucleophilic reactions. The stability and charge delocalization of the molecule were also considered by natural bond orbital (NBO) analysis. The HOMO-LUMO energies describe the charge transfer which takes place within the molecule. Molecular electrostatic potential has also been analysed. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. Molecular docking studies are implemented to analyse the binding energy of the DDFDI compound against Covid-19/6W41, COVID-19/6WCF, COVID-19/6Y84 and COVID-19/6W4B receptors and found to be considered as a better antiviral agents.

Synthesis and greener pastures biological study of bis-thiadiazoles as potential Covid-19 drug candidates.

A novel series of bis- (Abdelhamid et al., 2017, Banerjee et al., 2018, Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2'-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a-i to two COVID-19 important proteins Mpro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with Mpro was (-9.2 kcal/mol), followed by 6b and 6a, (-8.9 and -8.5 kcal/mol), respectively. The lowest recorded binding affinity was (-7.0 kcal/mol) for 6 g. In comparison, the approved drugs showed binding affinity (-7.4 and -7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (-8.6 kcal/mol), followed by 6a, 6 h, and 6i are the same have (-8.2 kcal/mol). The lowest reading was found for compound 3 ligand (-6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral Mpro. The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d, 6b, 6 g, and Remdesivir with 1-4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3, 6c, 6 h, and 6i gave 1-3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h. Pro Tox-II estimated compounds' activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin.

Exploration of Novel Lichen Compounds as Inhibitors of SARS-CoV-2 Mpro: Ligand-Based Design, Molecular Dynamics, and ADMET Analyses.

In the year 2019-2020, the whole world witnessed the spread of a disease called COVID-19 caused by SARS-CoV-2. A number of effective drugs and vaccine has been formulated to combat this outbreak. For the development of anti-COVID-19 drugs, the main protease (Mpro) is considered a key target as it has rare mutations and plays a crucial role in the replication of the SARS CoV-2. In this study, a library of selected lichen compounds was prepared and used for virtual screening against SARS-CoV-2 Mpro using molecular docking, and several hits as potential inhibitors were identified. Remdesivir was used as a standard inhibitor of Mpro for its comparison with the identified hits. Twenty-six compounds were identified as potential hits against Mpro, and these were subjected to in silico ADMET property prediction, and the compounds having favorable properties were selected for further analysis. After manual inspection of their interaction with the binding pocket of Mpro and binding affinity score, four compounds, namely, variolaric acid, cryptostictinolide, gyrophoric acid, and usnic acid, were selected for molecular dynamics study to evaluate the stability of complex. The molecular dynamics results indicated that except cryptostictinolide, all the three compounds made a stable complex with Mpro throughout a 100-ns simulation time period. Among all, usnic acid seems to be more stable and effective against SARS-CoV-2 Mpro. In summary, our findings suggest that usnic acid, variolaric acid, and gyrophoric acid have potential to inhibit SARS-Cov-2 Mpro and act as a lead compounds for the development of antiviral drug candidates against SARS-CoV-2.

Computational studies on potential new anti-Covid-19 agents with a multi-target mode of action.

A compound that could inhibit multiple targets associated with SARS-CoV-2 infection would prove to be a drug of choice against the virus. Human receptor-ACE2, receptor binding domain (RBD) of SARS-CoV-2 S-protein, Papain-like protein of SARS-CoV-2 (PLpro), reverse transcriptase of SARS-CoV-2 (RdRp) were chosen for in silico study. A set of previously synthesized compounds (1-5) were docked into the active sites of the targets. Based on the docking score, ligand efficiency, binding free energy, and dissociation constants for a definite conformational position of the ligand, inhibitory potentials of the compounds were measured. The stability of the protein-ligand (P-L) complex was validated in silico by using molecular dynamics simulations using the YASARA suit. Moreover, the pharmacokinetic properties, FMO and NBO analysis were performed for ranking the potentiality of the compounds as drug. The geometry optimizations and electronic structures were investigated using DFT. As per the study, compound-5 has the best binding affinity against all four targets. Moreover, compounds 1, 3 and 5 are less toxic and can be considered for oral consumption.

Multi-target potential of Indian phytochemicals against SARS-CoV-2: A docking, molecular dynamics and MM-GBSA approach extended to Omicron B.1.1.529.

BACKGROUND: SARS-CoV-2, an emerged strain of corona virus family became almost serious health concern worldwide. Despite vaccines availability, reports suggest the occurrence of SARS-CoV-2 infection even in a vaccinated population. With frequent evolution and expected multiple COVID-19 waves, improved preventive, diagnostic, and treatment measures are required. In recent times, phytochemicals have gained attention due to their therapeutic characteristics and are suggested as alternative and complementary treatments for infectious diseases. This present study aimed to identify potential inhibitors against reported protein targets of SARS-CoV-2. METHODOLOGY: We computationally investigated potential SARS-CoV-2 protein targets from the literature and collected druggable phytochemicals from Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Further, we implemented a systematic workflow of molecular docking, dynamic simulations and generalized born surface area free-energy calculations (MM-GBSA). RESULTS: Extensive literature search and assessment of 1508 articles identifies 13 potential SARS-CoV-2 protein targets. We screened 501 druggable phytochemicals with proven biological activities. Analysis of 6513(501 *13) docked phytochemicals complex, 26 were efficient against SARS-CoV-2. Amongst, 4,8-dihydroxysesamin and arboreal from Gmelina arborea were ranked potential against most of the targets with binding energy ranging between - 10.7 to - 8.2 kcal/mol. Additionally, comparative docking with known drugs such as arbidol (-6.6 to -5.1 kcal/mol), favipiravir (-5.5 to -4.5 kcal/mol), hydroxychloroquine (-6.5 to -5.1 kcal/mol), and remedesivir (-8.0 to -5.3 kcal/mol) revealed equal/less affinity than 4,8-dihydroxysesamin and arboreal. Interestingly, the nucleocapsid target was found commonly inhibited by 4,8-dihydroxysesamin and arboreal. Molecular dynamic simulation and Molecular mechanics generalized born surface area (MM-GBSA)calculations reflect that both the compounds possess high inhibiting potential against SARS-CoV-2 including the recently emerged Omicron variant (B.1.1.529). CONCLUSION: Overall our study imparts the usage of phytochemicals as antiviral agents for SARS-CoV-2 infection. Additional in vitro and in vivo testing of these phytochemicals is required to confirm their potency.

Crystal Growth, Structural, Vibrational, Effects of Hydrogen Bonding(C-H…O and C-H…N), Chemical Reactivity, Antimicrobial Activity, Inhibitory Effects and Molecular Dynamic Simulation of 4-Methoxy-N-(Nitrobenzylidene)-Aniline

The present study aims to provide deeper knowledge about the structural, vibrational, chemical, antimicrobial activity, molecular dynamic simulation and drug likeness of synthesized compound 4-Methoxy-N-(nitrobenzylidene)-aniline. The FT-IR and FT-Raman spectra of 4-Methoxy-N-(nitrobenzylidene)-aniline have been recorded in the powder form in the region 4000–500 cm−1 and 3500–50 cm−1. The vibrational analysis were carried out with the help of normal coordinate analysis (NCA). The molecular geometry, hydrogen bonding interaction and vibrational frequencies have been calculated using the density functional method (DFT/B3LYP) with 6-311 G (D) basis set. The natural bond orbital (NBO), atoms in molecule (AIM), and Hirshfeld surface analysis and RDG were applied to evaluate the relative strength of hydrogen bond interactions and represent their effect on the stabilities of molecular arrangements. Related molecules were compared by computation in order to understand the effect of non-bonded interactions (i.e. intermolecular and intramolecular hydrogen bonding). The HOMO and LUMO analysis was used to determine the charge transfer within the molecule. Furthermore, the in vitro antimicrobial study was carried out for the title compound against Aspergillus niger and Staphylococcus aureus. The antimicrobial activity was confirmed on the compounds with molecular docking (A.niger, S.aureus, Homosapians, Sars-Cov-19 and anticancer) studies and molecular dynamic simulation. The non-linear optical (NLO) properties were also analyzed for the molecules.

Crystal Growth, Structural, Vibrational, Effects of Hydrogen Bonding(C-H horizontal ellipsis O and C-H horizontal ellipsis N), Chemical Reactivity, Antimicrobial Activity, Inhibitory Effects and Molecular Dynamic Simulation of 4-Methoxy-N-(Nitrobenzylidene)-Aniline

The present study aims to provide deeper knowledge about the structural, vibrational, chemical, antimicrobial activity, molecular dynamic simulation and drug likeness of synthesized compound 4-Methoxy-N-(nitrobenzylidene)-aniline. The FT-IR and FT-Raman spectra of 4-Methoxy-N-(nitrobenzylidene)-aniline have been recorded in the powder form in the region 4000-500 cm(-1) and 3500-50 cm(-1). The vibrational analysis were carried out with the help of normal coordinate analysis (NCA). The molecular geometry, hydrogen bonding interaction and vibrational frequencies have been calculated using the density functional method (DFT/B3LYP) with 6-311 G (D) basis set. The natural bond orbital (NBO), atoms in molecule (AIM), and Hirshfeld surface analysis and RDG were applied to evaluate the relative strength of hydrogen bond interactions and represent their effect on the stabilities of molecular arrangements. Related molecules were compared by computation in order to understand the effect of non-bonded interactions (i.e. intermolecular and intramolecular hydrogen bonding). The HOMO and LUMO analysis was used to determine the charge transfer within the molecule. Furthermore, the in vitro antimicrobial study was carried out for the title compound against Aspergillus niger and Staphylococcus aureus. The antimicrobial activity was confirmed on the compounds with molecular docking (A.niger, S.aureus, Homosapians, Sars-Cov-19 and anticancer) studies and molecular dynamic simulation. The non-linear optical (NLO) properties were also analyzed for the molecules.

Integrated bioinformatics-cheminformatics approach toward locating pseudo-potential antiviral marine alkaloids against SARS-CoV-2-Mpro.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with the most contagious variants, alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and Omicron (B.1.1.529) has continuously added a higher number of morbidity and mortality, globally. The present integrated bioinformatics-cheminformatics approach was employed to locate potent antiviral marine alkaloids that could be used against SARS-CoV-2. Initially, 57 antiviral marine alkaloids and two repurposing drugs were selected from an extensive literature review. Then, the putative target enzyme SARS-CoV-2 main protease (SARS-CoV-2-Mpro) was retrieved from the protein data bank and carried out a virtual screening-cum-molecular docking study with all candidates using PyRx 0.8 and AutoDock 4.2 software. Further, the molecular dynamics (MD) simulation of the two most potential alkaloids and a drug docking complex at 100 ns (with two ligand topology files from PRODRG and ATB server, separately), the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) free energy, and contributions of entropy were investigated. Then, the physicochemical-toxicity-pharmacokinetics-drug-likeness profiles, the frontier molecular orbitals energies (highest occupied molecular orbital, lowest unoccupied molecular orbital, and ΔE), and structural-activity relationship were assessed and analyzed. Based on binding energy, 8-hydroxymanzamine (-10.5 kcal/mol) and manzamine A (-10.1 kcal/mol) from all alkaloids with darunavir (-7.9 kcal/mol) and lopinavir (-7.4 kcal/mol) against SARS-CoV-2-Mpro were recorded. The MD simulation (RMSD, RMSF, Rg, H-bond, MM/PBSA binding energy) illustrated that the 8-hydroxymanzamine exhibits a static thermodynamic feature than the other two complexes. The predicted physicochemical, toxicity, pharmacokinetics, and drug-likeness profiles also revealed that the 8-hydroxymanzamine could be used as a potential lead candidate individually and/or synergistically with darunavir or lopinavir to combat SARS-CoV-2 infection after some pharmacological validation.

Synthesis, crystal structure elucidation, DFT analysis, drug-likeness and ADMET evaluation and molecular docking studies of triazole derivatives: Binary inhibition of spike protein and ACE2 receptor protein of COVID-19.

The recent incidence of terrible acute respiratory syndrome coronavirus 2 (SARS CoV-2) has presently experienced some noteworthy mutations since its discovery in 2019 in Wuhan, China. The present research work focuses on the synthesis of three triazole derivatives (BMTPP, BMTTP, and BMTIP) and their inhibition activities against SARS-Cov-2 spike and ACE2 receptor proteins. The crystal structure for BMTTP was determined by the SCXRD method and optimized geometrical parameters for the three triazole derivatives were obtained by DFT calculations. HOMO-LUMO, Global reactive descriptors [GRD], and Molecular electrostatic potential (MEP) investigations exposed that all three compounds have biological properties. The drug-likeness ability of the synthesized compounds was examined using Molinspiration and a pre-ADMET online Server. Further, to explore the binding nature of three synthesized compounds with SARS-Cov-2 spike proteins/ACE2 receptor molecular docking studies were executed. The outcomes we obtained from molecular docking simulation studies suggest that the synthesized triazole derivatives may be well utilized as curing medicines against COVID-19. Ultimately, animal tests and precise clinical tests are required to prove the potent nature of these compounds against COVID-19. Finally, the present outcomes must be proved to utilize in-vitro and in-vivo antiviral methods.