COVID-19 Main Protease Research Articles

Crystal structure, Hirshfeld surface analysis, DFT and molecular docking studies of ethyl 5-amino-2-bromoisonicotinate

In the title compound, C8H9BrN2O2, the C—O—C—C torsion angle between isonicotine and the ethyl group is 180.0 (2)°. Intramolecular N—H...O and C—H...O interactions consolidate the molecular structure. In the crystal, N—H...N interaction form S(5) zigzag chains along [010]. The most significant contributions to the Hirshfeld surface arise from H...H (33.2%), Br...H/H...Br (20.9%), O...H/H...O (11.2%), C...H/H...C (11.1%) and N...H/H...N (10%) contacts. The topology of the three-dimensional energy frameworks was generated using the B3LYP/6–31 G(d,p) model to calculate the total interaction energy. The net interaction energies for the title compound are E ele = 59.2 kJ mol−1, E pol = 15.5 kJ mol−1, E dis = 140.3 kJ mol−1 and E rep = 107.2 kJ mol−1 with a total interaction energy E tot of 128.8 kJ mol−1. The molecular structure was optimized by density functional theory (DFT) at the B3LYP/6–311+G(d,p) level and the theoretical and experimentally obtained parameters were compared. The frontier molecular orbitals HOMO and LUMO were generated, giving an energy gap ΔE of 4.0931 eV. The MEP was generated to identify active sites in the molecule and molecular docking studies carried out with the title compound (ligand) and the covid-19 main protease PDB ID: 6LU7, revealing a moderate binding affinity of −5.4 kcal mol−1.

Synthesis, Docking Study of Some Novel Chromeno[4',3'-b]Pyrano [6,5-d]Pyrimidine Derivatives Against COVID-19 Main Protease (Mpro) (6LU7, 6M03).

In this work, some new chromeno[4',3'-b]pyrano[6,5-d]pyrimidines,3-amino and 3-methyl-5-aryl-4-imino-5(H)-chromeno[4',3'-b]pyrano[6,5-d]pyrimidine-6-ones derivatives were synthesized. Chromenopyrimidines have attracted significant attention recently because of their activities, such as antiviral and cytotoxic activity. All synthesized compounds were characterized using IR, 1H-NMR, Mass Spectroscopy, and elemental analysis data. Molecular docking studies were carried out to determine the inhibitory action of studied ligands against the Main Protease (6LU7, 6m03) of coronavirus (COVID-19). Moreover, the Lipinski Rule parameters were calculated for the synthesized compounds. The result of the docking studies showed a significant inhibitory action against the Main protease (Mpro) of SARS-CoV-2, and the binding energy (ΔG) values of the ligands against the protein (6LU7, 6M03) are -7.8 to -9.9 Kcal/mole. It may conclude that some ligands were likely to be considered lead-like against the main protease of SARS-CoV-2.

β-amino alcohols as promising inhibitory candidates against the SARS-CoV-2, A theoretical design based on MD simulation and DFT insights

Nelfinavir, as a compound with a Chiral β-amino alcohol unit, is a well-known inhibitor against HIV-protease, studying. The role of heterocyclic derivatives of Nelfinavir as inhibitors against the Main-Protease of COVID-19 is the main purpose of this study. To reach a deep understanding, different theoretical approaches including molecular docking, Molecular Dynamic (MD) simulations, and DFT insights are applied in the studies. Investigation of the ligand bioactivity reveals that smaller HOMO/LUMO band gaps and lower chemical hardness (η), mean stronger interaction with the active site of the Main-Protease for the corresponding β-amino alcohols. Analyzing the efficient interactions in binding energy shows that among the studied Chiral β-amino alcohols, formed Van der Waals interactions via π and alkyl parts of ligands have more remarkable roles in inhibitory effects than hydrogen bonding. Accordingly, molecular mechanics (MM) and polar interactions have the highest contributions to the total energy of residues. Finally, it has been concluded that among the studied derivatives those that contain Dihydroisoquinoline (4b), and Perhydroisoquinoline (4d) heterocyclic rings can be considered as more potent candidates against Main-Protease of COVID-19.

In-Silico Screening of Natural Compound Library against COVID-19 Main Protease

Aims: To perform in-silico screening of the natural phytoconstituents against COVID-19 main protease Background: COVID-19 is an atypical virus that is universal around the globe. WHO (World Health Organization) has also affirmed the emergency public health concerns regarding COVID-19. As COVID-19 spreads globally within a shorter duration, there is a great demand for effective therapy with minimal side effects. Objective: To perform SP and XP docking of the naturally obtained ligand Quercetin (flavonoid) based on HTVS. To identify the effectiveness of natural phytoconstituents for COVID-19 main protease virus. Methods: In the present study, natural ligands were used for performing the virtual screening, which was obtained from Prestwick Phytochemical Library by applying hierarchal screening. Several docking protocols, such as SP and XP, are used to screen the best natural hit compounds. The three best-hit compounds and hydroxychloroquine were further studied for SAR analysis. Moreover, the ADME study by QikProp and the identification of biological sources were carried out by Duke's Phytochemical and Ethnobotanical Databases. result: The results suggest that Quercetin showed good binding affinity towards 6LU7 (-56.689 kcal/mol) which could be the effective natural compound for COVID-19. Results: The results suggest that Quercetin showed good binding affinity towards 6LU7 (-56.689 kcal/mol), which could be an effective natural phytoconstituent for COVID-19. Conclusion: Based on HTVS, SP, and XP docking, the naturally obtained ligand Quercetin (a flavonoid) can be used in place of Hydroxychloroquine against COVID-19's main protease virus. This scientific exploration will help to identify the effective natural compound for the COVID-19 main protease virus.

Comprehensive analysis of Indacaterol and Theophylline molecules: insights from DFT, FTIR, Raman, UV, molecular docking, and ADMET studies

In this study, the structural, vibrational, and biological properties of Indacaterol and Theophylline were thoroughly investigated using quantum chemical and spectroscopic methods, and then compared with experimental FTIR, Raman, and UV–Vis data. The analysis revealed that electronegative oxygen and nitrogen atoms in both molecules facilitate charge transfers, resulting in the shortening of C–C bonds. The HOMO–LUMO energy gaps were found to be 4.298 eV for Indacaterol and 5.170 eV for Theophylline, indicating that Indacaterol is more bioactive. The electrophilic index values suggest that Indacaterol is more electrophilic, potentially offering a higher affinity for protein binding. Molecular electrostatic potential surface maps indicated that electrophilic regions are concentrated near the oxygen and nitrogen atoms, which was corroborated by molecular docking analysis. Binding affinities of Indacaterol and Theophylline to COVID-19 main protease proteins were calculated, showing higher affinities for Indacaterol. Drug likeness, physicochemical, and ADMET results suggest that both molecules have favorable pharmacokinetic profiles and comply with Lipinski’s Rule of Five, indicating effective absorption and distribution. Overall, the study suggests that Indacaterol and Theophylline could function as inhibitors against SARS-CoV-2 and COVID-19 proteins, with Indacaterol potentially being more effective.

Rational Approach toward COVID-19's Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis.

This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from -6.2 to -9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein-ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.

New Pyrimidinone Bearing Aminomethylenes and Schiff Bases as Potent Antioxidant, Antibacterial, SARS-CoV-2, and COVID-19 Main Protease MPro Inhibitors: Design, Synthesis, Bioactivities, and Computational Studies.

New 2-thioxopyrimidinone derivatives (A1-A10) were synthesized in 87-96% yields via a simple three-component condensation reaction. These compounds were screened extensively through in vitro assays for antioxidant and antibacterial investigations. The DPPH assays resulted in the excellent potency of A6-A10 as antioxidants with IC50 values of 0.83 ± 0.125, 0.90 ± 0.77, 0.36 ± 0.063, 1.4 ± 0.07, and 1.18 ± 0.06 mg/mL, which were much better than 1.79 ± 0.045 mg/mL for the reference ascorbic acid. These compounds exhibited better antibacterial potency against Klebsiella with IC50 values of 2 ± 7, 1.32 ± 8.9, 1.19 ± 11, 1.1 ± 12, and 1.16 ± 11 mg/mL for A6-A10. High-throughput screenings (HTS) of these motifs were carried out including investigation of drug-like behaviors, physiochemical property evaluation, and structure-related studies involving DFT and metabolic transformation trends. The radical scavenging ability of the synthesized motifs was validated through molecular docking studies through ligand-protein binding against human inducible nitric oxide synthase (HINOS) PDB ID: 4NOS, and the results were promising. Furthermore, the antiviral capability of the compounds was examined by in silico studies using two viral proteins PDB ID: 6Y84 and PDB ID: 6LU7. Binding poses of ligands were discussed, and amino acids in the protein binding pockets were investigated, where the tested compounds showed much better binding affinities than the standard inhibitors, proving to be suitable leads for antiviral drug discovery. The stabilities of the molecular docked complexes in real systems were validated by molecular dynamics simulations.

2,4-dichloro-6-(1,4,5-triphenyl-1H-imidazol-2-yl) phenol: synthesis, DFT analysis, Molecular docking, molecular dynamics, ADMET properties against COVID-19 main protease (Mpro: 6WCF/6Y84/6LU7)

ABSTRACT New derivatives of 2,4-dichloro-6-(1,4,5-triphenyl-1H-imidazol-2-yl) phenol (DPIP) have been successfully synthesised and characterised using spectral methods such as FT-IR, 1H NMR and 13C NMR. Density functional theory (DFT) approach at B3LYP/6-311 G (d, p) level of theory is used to determine optimised bond parameters and single crystal XRD investigation of related derivatives confirms the structure of DPIP bond parameters. The single crystal XRD measurements and the optimised geometrical parameters produced by the DFT calculation agree well. The FT-IR bands seen in the experiment were attributed to distinct normal modes of the molecule. Frontier molecular orbital computations described the molecule stability, chemical reactivity and charge transfer. Atomic charges determined via Mulliken population analysis on the different DPIP atoms. MEP, which is mapped to the electron density surfaces, has discovered potential reactive sites of the molecule. The reported molecule is used as a potential NLO material since it has a high μβ0 value. Binding affinities were discovered using molecular docking against the COVID-19 major protease (Mpro: 6WCF/6Y84/6LU7). The behaviour of the complex structure formed by the Covid-19 protein under in silico physiological conditions was then confirmed by a 100 ns molecular dynamic simulation which looked at the structure stability over time and revealed a stable conformation and binding pattern in an environment of imidazole derivatives. Furthermore, favourable to moderate anti-viral activity was revealed by an in-silico analysis that anticipated the compound absorption, distribution, metabolism, excretion and toxicity profiles (ADMET).

Synthesis and in silico inhibitory action studies of azo-anchored imidazo[4,5-b]indole scaffolds against the COVID-19 main protease (Mpro)

The present work elicits a novel approach to combating COVID-19 by synthesizing a series of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives. The envisaged methodology involves the l-proline-catalyzed condensation of para-amino-functionalized azo benzene, indoline-2,3-dione, and ammonium acetate precursors with pertinent aryl aldehyde derivatives under ultrasonic conditions. The structures of synthesized compounds were corroborated through FT-IR, 1H NMR, 13C NMR, and mass analysis data. Molecular docking studies assessed the inhibitory potential of these compounds against the main protease (Mpro) of SARS-CoV-2. Remarkably, in silico investigations revealed significant inhibitory action surpassing standard drugs such as Remdesivir, Paxlovid, Molnupiravir, Chloroquine, Hydroxychloroquine (HCQ), and (N3), an irreversible Michael acceptor inhibitor. Furthermore, the highly active compound was also screened for cytotoxicity activity against HEK-293 cells and exhibited minimal toxicity across a range of concentrations, affirming its favorable safety profile and potential suitability. The pharmacokinetic properties (ADME) of the synthesized compounds have also been deliberated. This study paves the way for in vitro and in vivo testing of these scaffolds in the ongoing battle against SARS-CoV-2.

Synthesis, spectroscopic characterization, DFT analysis and molecular docking of Mn(II), Co(II) and Ni(II) complexes of hydrazone derived from 5-chloroisatin and 2,4-dinitrophenylhydrazine

Octahedral Co(II), Mn(II) and Ni(II) complexes have been synthesized with a tridentate ONC-donor hydrazone ligand 5‑chloro-3-(2-(2,4-dinitrophenyl)hydrazono)indolin-2-one (H2L). The chemical structures of the complexes were elucidated by spectroscopic methods. The spectral data show an octahedral geometry where a cyclometallation was formed through deprotonation of the 6-C-H carbon of the 2,4-dinitrophenyl ring with O and azomethine N coordinating to the metal atom. DFT calculations were used to investigate the structures and the electronic properties of the complexes and their optimized structures were generated. Molecular docking studies on the transmissible gastroenteritis virus protease (4F49) and the COVID-19 main protease (6LU7) revealed that Ni(II) complex displayed the highest binding affinity (-9.7 kcal/mol and -8.2 kcal/mol) to the active site of proteins 4F49 and 6LU7 respectively. The protein-complex interactions studied for all the compounds exhibit favourable binding affinities, surpassing the -5.0 kcal/mol threshold reported in the literature. These studies indicate that Ni(II), Co(II) and Mn(II) cyclometallated complexes of the hydrazone ligand are potential inhibitors of SARS-CoV-2 and the gastroenteritis virus.

Targeting COVID-19 (SARS-CoV-2) main protease through phytochemicals of Albizia lebbeck: molecular docking, molecular dynamics simulation, MM–PBSA free energy calculations, and DFT analysis

Targeting COVID-19 (SARS-CoV-2) main protease through phytochemicals of Albizia lebbeck: molecular docking, molecular dynamics simulation, MM–PBSA free energy calculations, and DFT analysis

Activity profiling of natural and synthetic SARS-Cov-2 inhibitors using molecular docking analysis

Abstract COVID-19, the global pandemic caused by SARS-Corona virus 2 (SARS-CoV-2), recently ravaged the World with various efforts charged towards finding therapeutic drug targets for this novel virus. The identification of COVID-19 main protease (Mpro) opened the possibility of testing new families of inhibitors as potential anti-coronaviral drugs. Protein-drug interaction is of pivotal importance to understanding the structural features essential for any ligand affinity. This study evaluated the efficacy of an isolated bioactive plant compound and synthetic tetraazamacrocycles against COVID-19 Mpro by molecular docking. Molecular docking investigations were performed using PyRx, Auto Dock vina and Discovery Studio (DS) to analyze the inhibition probability of these compounds against COVID-19. COVID-19 Mpro (PDB ID: 6LU7: Resolution 2.16 Å) was docked with 1 flavonoid and 3 tetraaza-macrocyclic compounds comparatively with known anti-viral drugs (Remdesivir (REMD) and Nelfinavir (NELF)) and hydroxychloroquine (HCQ). Docking studies showed H-TEAD, 5 interacting with 5 residues having the highest binding affinity of −9.4 kcal/mol, followed by TEAD with 5 residue interactions and a binding affinity value of −9.4 kcal/mol, HA-TEAD, 7 has 5 interactions with a binding affinity of −9.3 kcal/mol, and Siam1 has 6 interactions with a binding energy of −7.8 kcal/mol. All the docked potential drugs have binding energies higher than the reference drugs HCQ, 1 and REMD, 2 connoting greater activity except NELF, 3 whose value is only lower than the 3 macrocycles (HA-TEAD, 7 and H-TEAD, 5 and TEA1, 6). They are bound through hydrogen bonds, arene-anion and arene-cation interactions. The trend of binding affinity show H-TEAD (−9.4 kcal/mol) = TEAD1 (−9.4 kcal/mol) > HA-TEAD (−9.3 kcal/mol) > NELF (−8.7 kcal/mol) > Siamone (−8.8 kcal/mol) > HCQ (−7.2 kcal/mol) > REMD (−6.2 kcal/mol) while the number of interactions shows REMD > HA-TEAD = HCQ > Siamone > NELF > H-TEAD > TEAD1. This study, hence, validates the activity of HCQ against COVID-19 and provides a foundation for advanced experimental research, to evaluate the real pharmaceutical potentials of these compounds, towards finding a cure for COVID-19 and other related diseases.

Computational Approaches Molecular Docking and MD Simulation Establishes the Potential COVID-19 Main Protease Inhibitors from Natural Products

Aim: COVID-19 was classified as a pandemic by the World Health Organization (WHO) on March 11, 2020. No reliable cure, however, was found. To prevent viral replication, complementary therapy with antiviral and antimalarial medications were used. However, due to their synthetic origin, they have a lot of side effects. To overcome this bane natural origin drugs were repositioned. Background: As repositioned drugs do not undergo a pro-long process of pre-clinical trial, hence, they play an excellent role in the spillover of pathogens. The main protease (6LU7) enzyme found in severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) is essential for viral replication. Thus, it acts as a hotspot in drug discovery. Objective: A molecular docking computational approach was used to determine the ability of the binding contract between the selected 3D-models of COVID-19 protease target and proposed natural compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene,and β-sitosterol through Autodock v.1.5.6 software. Method: The present study is designed to perform in-silico studies using molecular docking (Autodock tool v.1.5.6), Discovery Studio 2017 R2 client, Patch dock, SWISS-ADME prediction, and molecular simulation (Desmond simulation package of Schrodinger) between 6LU7 and natural origin compounds. Result: The results of docking study performed between 6LU7 and compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene, and β-sitosterol, showed binding energy as -9.68, -7.34, -5.34, -4.63, -4.24, -4.13, -4.08, -3.85, -3.83, -3.7, -3.6, -3.57, -3.54, -3.39, -3.18, and -3.03 Kcal/mol, respectively. It can be shown that the Pristimerin-6LU7 protein complex was maintained throughout the simulation since the ligand RMSDs varied with a maximum value of 4.2Å during the first 10 ns, followed by more stable interactions for the remaining time of the simulation. Conclusion: The goal of the current work was to find inhibitors for both prophylactic and therapeutic usage in COVID-19 patients.

A novel pyrazole derivative as COVID-19 main protease inhibitor: Synthesis, quantum computational studies, pharmacokinetic properties, drug likeness, molecular docking and dynamics simulation; a CADD approach

2-(3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-4H benzo[d][1,3]oxazin-4-one (2-BCBO) compound, was synthesized by the reaction of 3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in acetonitrile and methane sulfonyl chloride. The monoclinic crystal structure in C2/c space group of the compound was unveiled through single-crystal X-ray diffraction studies. A prediction model was employed to investigate the influence of intermolecular contacts on molecular packing in the crystalline phase. The model incorporated both Hirshfeld surface and 2D fingerprint models to gain a comprehensive understanding of the strength of these contacts. The calculation of the total interaction energy was conducted by utilizing the three-dimensional molecular energy frameworks and further, employed density functional theory to examine molecular orbital characteristics and key factors associated with chemical reactivity. The application of topological analysis techniques, such as QTAIM and NCI, provided further insight regarding the attraction and repulsive interactions shown by the molecule. The pharmacokinetic properties of the 2-BCBO molecule have also been examined using ADMET analysis, which is important in drug discovery and development. In addition, the molecular docking study to determine the inhibitory effect of the investigated ligand on the main protease of new coronavirus (COVID-19), followed by molecular dynamics simulations, and it is found that both the results are in good agreement. The 2-BCBO could be accepted as a lead molecule to treat the coronavirus.

Prediction of In-silico ADMET Properties and Molecular docking study of Substituted Thiadiazole for screening of Antiviral activity against protein target Covid-19 main protease

The SARS-CoV-2 virus is the infectious disease known as coronavirus disease (COVID-19). The majority of COVID-19 patients will have mild to moderate symptoms and recover without additional care. However, some people will get serious illnesses and need medical attention. Designing novel medications and testing them for inhibitory action against the corona virus's primary targets could be a successful technique for the advancement of the drug discovery process and the treatment of corona virus disease in the context of the COVID-19 pandemic, which is spreading quickly. The objective of this work was to evaluate the physical-chemical, pharmacokinetic parameters (absorption, distribution, metabolism, excretion and toxicity) and pharmacodynamic parameters (bioactivity and adverse reactions) of Substituted thiadiazole by means of in-silico computational prediction. Online software such as Pre-ADMET, Molinspiration and Rule of Five were used for the analysis. In-silico results allow us to conclude that substituted thiadiazole is predicted to be a potential future drug candidate, due to its relevant Drug-likeness profile, bioavailability, excellent liposolubility and adequate pharmacokinetics, including at the level of CNS, penetrating the blood-brain barrier. Molecular docking studies of 20 designed compounds have also been performed to screen the inhibitory activity towards against protein target COVID-19 main protease (PDB: 6LU7). Among all the compounds C3 exhibited the most significant affinity score against COVID-19 main protease (PDB: 6LU7) and Shown best significant hydrogen bonds interaction at the active site of protein.

Synthesis, quantum chemical studies, molecular docking, molecular dynamics simulation and ADMET studies on 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1, 4,5-triphenyl-1H-imidazole derivatives

A novel 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4,5-triphenyl-1H-imidazole (DDTI) molecule was synthesised and characterised by FT-IR and NMR (1H and 13C) spectral techniques. The molecular structure was optimised using the density functional theory (DFT) method with B3LYP/6-311 G (d, p) basis set. Natural bonding orbital (NBO) analysis was used to determine the electron densities of donor (i) and acceptor (j) bonds as well as the hyperconjugative interaction energy (E ( 2) ). In highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) calculations, the smaller energy gap value was discovered. Molecular electrostatic potential has been analysed. The Mulliken atomic charges of the carbon, nitrogen and oxygen atoms were calculated at the same level of theory. The dipole moment, polarizability and first-order hyperpolarizability demonstrate the good nonlinear optical (NLO) feature of the title molecule. Molecular docking studies are implemented to analyse the binding energy of the DDTI compound against standard drugs such as the crystal structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES, SARS-CoV-2 main protease with an unliganded active site (2019-nCoV, corona virus disease 2019, COVID-19) and the crystal structure of COVID-19 main protease in complex with an inhibitor N3 found to be considered having better antiviral agent. Molecular dynamics simulation was performed for COVID-19 main protease (Mpro: 6WCF/6Y84/6LU7) to understand the elements governing the inhibitory effect and the stability of interactions under dynamic conditions. Virtual ADMET studies were carried out as well and a relationship between biological, electronic and physicochemical qualifications of the target compound was determined. Toxicity prediction by computational technique for the title compound was also carried out.

A Molecular Generative Model of COVID-19 Main Protease Inhibitors Using Long Short-Term Memory-Based Recurrent Neural Network.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious threat to public health and prompted researchers to find anti-coronavirus 2019 (COVID-19) compounds. In this study, the long short-term memory-based recurrent neural network was used to generate new inhibitors for the coronavirus. First, the model was trained to generate drug compounds in the form of valid simplified molecular-input line-entry system strings. Then, the structures of COVID-19 main protease inhibitors were applied to fine-tune the model. After fine-tuning, the network could generate new molecular structures as novel SARS-CoV-2 main protease inhibitors. Molecular docking exhibited that some generated compounds have the proper affinity to the active site of the protease. Molecular Dynamics simulations explored binding free energies of the compounds over simulation trajectories. In addition, in silico absorption, distribution, metabolism, and excretion studies showed that some novel compounds could be formulated as orally active agents. Based on molecular docking and molecular dynamics simulation studies, compound AADH possessed significant binding affinity and presumably inhibition against the SARS-CoV-2 main protease enzyme. Therefore, the proposed deep learning-based model was capable of generating promising anti-COVID-19 drugs.

Molecular Docking Analysis of SARS-CoV-2 Inhibitor N3 (6LU7) against Selected Flavonoids and Vitamins

<p>Background: Coronavirus is a zoonotic disease and transmits between animals and humans. The disease known as COVID-19 (SARS-CoV-2) has become a pandemic since its outbreak. In addition to vaccines, a combination of antiretroviral agents, chloroquine derivatives, and vitamins are being used to treat SARS-CoV-2. <p> Method: We performed molecular docking analysis of SARS-CoV-2 inhibitor N3 (6LU7) using a series of flavonoid derivatives and vitamins. The X-ray crystallographic 3D structures of COVID-19 main protease in complex with an inhibitor N3 (PDB code: 6LU7, resolution 2.16 Å complexed with a selective substance) were downloaded from the online Protein Data Bank. The structures of the ligands and protein were constructed using ChemDrawUltra 8.0. The docking process, interactions, and binding of ligands were visualized using the software Molegro Virtual Dockings (MVD). The physicochemical and toxicity characteristics of tested flavonoid derivatives and vitamins were determined using Swiss-ADME and pkCSM online software. We found that molecular docking scores were between -64.42 and –172.00 Kcal/mol. The H-bonding and steric interactions were compared with other flavonoid derivatives. The ADMET parameters suggested that compounds 4, 68, 90, 92, and 94 have a higher GI rate. <p> Results: Our results also indicated that compound 78 was more potent and had higher skin permeation than other flavonoid derivatives. The study showed that the compounds 5, 28, 74, 78, and folic acid fitted well in the active site of COVID-19 inhibitor N3 (6LU7) and interacted with the residues in the active site, which are essential for their biological activity. <p> Conclusion: Therefore, compounds 5, 28, 74, and 78 and folic acid can be a COVID-19 inhibitor N3 (6LU7) and might be used in the treatment of COVID-19 infection.</p>

Self-assembly, virtual screening of a new cobalt complex: Synthesis, empirical, DFT calculations, biological activity investigations and identification of inhibitory activity on the main protease of COVID-19 and SARS-CoV2 by molecular docking strategy of (C6H6NF)2[Co(SCN)2

The present work undertakes the study of a new thiocyanic complex (C6H6NF)2[Co(SCN)2], a synergy between the two experimental and theoretical approach allows us to characterize and evaluate our crystal. (C6H6NF)2[Co(SCN)2] has been successfully synthesized at room temperature by slow evaporation and crystallized in monoclinic system with P21/c space group, in addition the X-ray powder diffraction to punctuate the obtention of a pure phase of the desired complex. Infrared spectrum was registered to revel the vibrational modes of the coordination compound. To highlight the optical properties, the UV–visible analysis was performed using a polar solvent. Thermal analyses were carried out to account for the thermal decomposition of complex. In order to gain insights into the role of weak molecular interactions in the complex that influence the self-assembly process and crystal packing, Hirshfeld surface analysis and DFT calculation were also performed. Furthermore, molecular docking and molecular dynamic simulations were performed for the compounds against different antibacterial targets to identify to which target the compounds show the best binding affinity. The MurF enzyme, which catalyzed the last cytoplasmic step of bacterial peptidoglycan synthesis, among the target was revealed to show better interactions with the enzyme and formed strong and stable intermolecular complex. Molecular docking analysis reveals that 1EPBN might display the inhibitory activity against coronavirus proteins (COVID-19 and SARS-CoV2).

Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2.

Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer's disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (-8.03, -8.65, and -8.68kcal/mol, respectively) over the co-crystal ligand O6K (-7.00kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood-brain barrier in PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27μM, 44.42 ± 0.30μM, and 42.74 ± 0.23μM respectively. In the PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19.