Design of novel isoxazole derivatives as tubulin inhibitors using computer-aided techniques: QSAR modeling, in silico ADMETox, molecular docking, molecular dynamics, biological efficacy, and retrosynthesis.

In the current work, computational methods were used to investigate new isoxazole derivatives that could be used as tubulin inhibitors. The study aims to develop a reliable quantitative structure-activity relationship (QSAR) model, following the criteria set by Golbraikh, Tropsha, and Roy. As a result, seven candidate compounds were developed, all having higher activity than the well-established anticancer agent Cisplatin (Cisp). According to the ADMETox in silico test, the candidates Pr4, Pr5, and P6 can be toxic. As a result, we have chosen to focus our study on compounds Pr1, Pr2, and Pr3. Molecular docking analysis revealed that drug candidate Pr2 exhibits the highest stability within the oxidized quinone reductase 2 (PDB ID: 4zvm), target receptor (ΔG(Pr2) = ΔG(Pr3) = -10.4 < ΔG(Pr1) = -10.0 < ΔG(Cisp) = -7.3 kcal/mol). This finding aligns with the activity predictions made by the QSAR model. Furthermore, molecular dynamics simulations of the Pr2-4zvm complex over 100 ns confirm the ligand's robust stability within the receptor's active site, supporting the results obtained from molecular docking and the QSAR model predictions. The CaverDock software was utilized to identify the tunnels likely to be followed by ligands moving from the active site to the receptor surface. This analysis also helped in determining the biological efficacy of the target compounds. The results indicated that the Pr2 compound is more effective than the others. Finally, the computer-assisted retrosynthesis process of two high confidence sequences was used to synthesize drug candidates.Communicated by Ramaswamy H. Sarma.

3D-QSAR methods were used to design eight new compounds and anti-tubulin agents.3D-QSAR models were validated by Golbraikh­Tropsha and Roy methods.The toxicity and pharmacokinetics of the proposed compounds were identified by the Lipinski rule of five, Veber rules, and ADMETox.Pr2 and Pr3 had a reasonable affinity to the receptor protein (ID PDB: 4zvm) based on molecular docking, reactivity indices, and molecular dynamics simulation.Metadynamics was used to study ligand transport in the receptor (ID PDB:3zvm).

Computational evaluation of 1,2,3-triazole-based VEGFR-2 inhibitors: anti-angiogenesis potential and pharmacokinetic assessment.

The vascular endothelial growth factor (VEGF) and its cell surface receptor, as well as the human VEGFR-2 domain kinase, are some of the signaling pathways that have received the most attention in this field. This study aimed to identify novel molecules as VEGFR-2 inhibitors using 3D-QSAR modeling based on 1,2,3-triazole. Docking studies and dynamic simulations were performed to analyze novel interactions with the inhibitors and validate the molecular docking, dynamic simulations, and ADMET analyses. The optimized CoMSIA/SEH model showed good statistical results, and molecular docking and molecular dynamics simulations demonstrated stability of M3 ligand with the receptor and provided insight into ligand-receptor interactions. The newly developed compounds performed well in ADMET evaluations and showed promising results using Lipinski's rule of five, suggesting that the molecule M3 could be a useful anti-angiogenesis agent. In conclusion, this study provides insights into the structure-activity relationship of VEGFR-2 inhibitors and identifies M3 as a potential new anti-angiogenesis drug. The methodology used in this study can be applied to other similar drug targets to discover new and potent inhibitors.Communicated by Ramaswamy H. Sarma.

Exploring azomethine ylides reactivity with acrolein through cycloaddition reaction and computational antiviral activity assessment against hepatitis C virus.

CONTEXT: The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor. METHODS: Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.

Molecular toxicity of nitrobenzene derivatives to tetrahymena pyriformis based on SMILES descriptors using Monte Carlo, docking, and MD simulations.

It is challenging to model the toxicity of nitroaromatic compounds due to limited experimental data. Nitrobenzene derivatives are commonly used in industry and can lead to environmental contamination. Extensive research, including several QSPR studies, has been conducted to understand their toxicity. Predictive QSPR models can help improve chemical safety, but their limitations must be considered, and the molecular factors affecting toxicity should be carefully investigated. The latest QSPR methods, molecular modeling techniques, machine learning algorithms, and computational chemistry tools are essential for developing accurate and robust models. In this work, we used these methods to study a series of fifty compounds derived from nitrobenzene. The Monte Carlo approach was used for QSPR modeling by applying the SMILES molecular structure representation and optimal molecular descriptors. The correlation ideality index (CII) and correlation contradiction index (CCI) were further introduced as validation parameters to estimate the developed models' predictive ability. The statistical quality of the CII models was better than those without CII. The best QSPR model with the following statistical parameters (Split-3): (R2 = 0.968, CCC = 0.984, IIC = 0.861, CII = 0.979, Q2 = 0.954, QF12 = 0.946, QF22 = 0.938, QF32 = 0.947, Rm2 = 0.878, RMSE = 0.187, MAE = 0.151, FTraining = 390, FInvisible = 218, FCalibration = 240, RTest2 = 0.905) was selected to generate the studied promoters with increasing and decreasing activity.

3D-QSAR, molecular docking, simulation dynamic and ADMET studies on new quinolines derivatives against colorectal carcinoma activity.

Cancer is the uncontrolled spread of abnormal cells that results in abnormal tissue growth in the affected organ. One of the most important organs is exposed to the growth of colon cancer cells, which start in the large intestine (colon) or the rectum. Several therapeutic protocols were used to treat different kinds of cancer. Recently, several studies have targeted tubulin and microtubules due to their remarkable prefoliation. Also, recent research shows that quinoline compounds have significant efficacy against human colorectal cancer. So, the present work investigated the potential of thirty quinoline compounds as tubulin inhibitors using computational methods. A 3D-QSAR approach using two contours (CoMFA and CoMSIA), molecular docking simulation to determine the binding type of the complexes (ligand-receptor), molecular dynamics simulation and identifying pharmacokinetic characteristics were used to design molecules. For all compounds designed (T1-5), molecular docking was used to compare the stability by type of binding. The ADMET has been utilized for molecules with good stability in molecular docking (T1-3); these compounds have good medicinal characteristics. Furthermore, a molecular dynamics simulation (MD) at 100 ns was performed to confirm the stability of the T1-3 compounds; the molecules (T1-3) remained the most stable throughout the simulation. The compounds T1, T2 and T3 are the best-designed drugs for colorectal carcinoma treatments.Communicated by Ramaswamy H. Sarma.

In silico research on new sulfonamide derivatives as BRD4 inhibitors targeting acute myeloid leukemia using various computational techniques including 3D-QSAR, HQSAR, molecular docking, ADME/Tox, and molecular dynamics.

Acute myeloid leukemia, a serious condition affecting stem cells, drives uncontrollable myeloblast proliferation, leading to accumulation. Extensive research seeks rapid, effective chemotherapeutics. A potential option is a BRD4 inhibitor, known for suppressing cell proliferation. Sulfonamide derivatives probed essential structural elements for potent BRD4 inhibitors. To achieve this goal, we employed 3D-QSAR molecular modeling techniques, including CoMFA, CoMSIA, and HQSAR models, along with molecular docking and molecular dynamics simulations. The validation of the 2D/3D QSAR models, both internally and externally, underscores their robustness and reliability. The contour plots derived from CoMFA, CoMSIA, and HQSAR analyses played a pivotal role in shaping the design of effective BRD4 inhibitors. Importantly, our findings highlight the advantageous impact of incorporating bulkier substituents on the pyridinone ring and hydrophobic/electrostatic substituents on the methoxy-substituted phenyl ring, enhancing interactions with the BRD4 target. The interaction mode of the new compounds with the BRD4 receptor (PDB ID: 4BJX) was investigated using molecular docking simulations, revealing favorable binding energies, supported by the formation of hydrogen and hydrophobic bonds with key protein residues. Moreover, these novel inhibitors exhibited good oral bioavailability and demonstrated non-toxic properties based on ADMET analysis. Furthermore, the newly designed compounds along with the most active one from series 58, underwent a molecular dynamics simulation to analyze their behavior. The simulation provided additional evidence to support the molecular docking results, confirming the sustained stability of the analyzed molecules over the trajectory. This outcome could serve as a valuable reference for designing and developing novel and effective BRD4 inhibitors.Communicated by Ramaswamy H. Sarma.

Computational Prediction of 3,5-Diaryl-1H-Pyrazole and spiropyrazolines derivatives as potential acetylcholinesterase inhibitors for alzheimer disease treatment by 3D-QSAR, molecular docking, molecular dynamics simulation, and ADME-Tox.

The efficacy of 40 synthesized variants of 3,5-diaryl-1H-pyrazole and spiropyrazoline' derivatives as acetylcholinesterase inhibitors is verified using a quantitative three-dimensional structure-activity relationship (3D-QSAR) by comparative molecular field analysis (CoMFA) and molecular similarity index analysis (CoMSIA) models. In this research, different field models proved that CoMSIA/SE model is the best model with high predictive power compared to several models (Qved2 = O.65; R2 = 0.980; R2test = 0.727). Also, contour maps produced by CoMSIA/SE model have been employed to prove the key structural needs of the activity. Consequently, six new compounds have been generated. Among these compounds, M4 and M5 were the most active but remained toxic and had poor absorption capacities. While the M1, M2, M3 and M6 remained highly active while respecting ADMET's characteristics. Molecular docking results showed compound M2 better with acetylcholinesterase than compound 22. The interactions are classical hydrogen bonding with residues TYR:124, TYR:72, and SER:293, which play a critical role in the biological activity as AChE inhibitors. MD results confirmed the docking results and showed that compound M2 had satisfactory stability with (ΔGbinding = -151.225 KJ/mol) in the active site of AChE receptor compared with compound 22 (ΔGbinding = -133.375 KJ/mol). In addition, both compounds had good stability regarding RMSD, Rg, and RMSF. The previous results show that the newly designed compound M2 is more active in the active site of AChE receptor than compound 22.Communicated by Ramaswamy H. Sarma.

Computational investigation of imidazo[2,1-b]oxazole derivatives as potential mutant BRAF kinase inhibitors: 3D-QSAR, molecular docking, molecular dynamics simulation, and ADMETox studies.

BRAF inhibitors are known to be an effective therapeutic target for treating melanoma and other types of cancer. Using 3D-QSAR, molecular docking, and MD simulations, this study evaluated various imidazo[2,1-b]oxazole derivatives that function as mutant BRAF kinase inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were used to create the 3D-QSAR models. CoMSIA/SEHA model has solid predictive power across several models (Q2 = 0.578; R2 = 0.828; R2pred = 0.74) and is the best model according to the numerous field models generated. The created model's predictive power was evaluated through external validation using a test set. CoMSIA/SEHA contour maps collect information that can be used to identify critical regions with solid anticancer activity. We developed four inhibitors with high predicted activity due to these observations. ADMET prediction was used to assess the toxicity of the proposed imidazo[2,1-b]oxazole compounds. The predictive molecules (T1-T4) demonstrated good ADMET properties, excluding the toxic active compounds 11r from the database. Molecular docking was also used to determine the patterns and modes of interactions between imidazo[2,1-b]oxazole ligands and receptors, which revealed that the proposed imidazo[2,1-b]oxazole scaffold was stable in the receptor's active site (PDB code: 4G9C). The suggested compounds (T1-T4) were subjected to molecular dynamics simulations lasting 100 ns to determine their binding free energies. The results showed that T2 had a more favorable binding free energy (-149.552 kJ/mol) than T1 (-112.556 kJ/mol), T3 (-115.503 kJ/mol), and T4 (-102.553 kJ/mol). The results suggest that the imidazo[2,1-b]oxazole compounds investigated in this study have potential as inhibitors of BRAF kinase and could be further developed as anticancer drugs. Highlights22 imidazo[2,1-b]oxazole compounds were subjected to research on three-dimensional quantitative conformational relationships.Using contour maps from 3D-QSAR models as a guide was used to figure out the areas and strategies for structural optimization.Combined molecular docking, molecular dynamics simulations, and binding free energy calculations to verify the inhibitor activity of the proposed 22 imidazo[2,1-b]oxazole compounds.Four potential B-RAF Kinase inhibitors were discovered, providing theoretical clues for developing a highly anticancer agent.Communicated by Ramaswamy H. Sarma.

Design new organic material based on triphenylamine (TPA) with D-π-A-π-D structure used as an electron donor for organic solar cells: A DFT approach.

Because of the increasing scarcity of fossil fuels and the growing need for energy, it has become necessary to research new renewable energy resources. In this study, five new high-performance materials (TP-FA1F-TP - TP-FA5F-TP) of the D-π-A-π-D configuration based on triphenylamine (TPA) were theoretically investigated by applying DFT and TD-DFT methods for future application as heterojunction organic solar cells (BHJ). The influence of the modification of the acceptor (A) of the parent molecule TP-FTzF-TP on the structural, electronic, photovoltaic and optical properties of the TP-FA1F-TP - TP-FA5F-TP organic molecules was investigated in detail. TP-FA1F-TP - TP-FA5F-TP showed Egap in the interval of 1.44-2.01 eV with λabs in the range of 536-774 nm, open-circuit voltage (Voc) values varied between 0.3 and 0.56 V and power conversion efficiencies (PCE) ranging from (3-6) %. Our results also show that the donor molecules suggested in this research exhibit an improved performance compared to the recently synthesized TP-FTzF-TP, such as a lowest HOMO energy, a smaller Egap, and a greater absorption spectrum, and can lead to higher performance. Indeed, this theoretical research could lead to the future synthesis of better compounds as active substances used in BHJ.

Profiling the structural determinants of pyrrolidine derivative as gelatinases (MMP-2 and MMP-9) inhibitors using in silico approaches.

Quantitative structure activity relationship (QSAR) studies on pyrrolidine derivatives have been established using CoMFA, CoMSIA, and Hologram QSAR analysis to estimate the values (pIC50) of gelatinase inhibitors. When the CoMFA cross-validation value, Q², was 0.625, the training set coefficient of determination, R² was 0.981. In CoMSIA, Q² was 0.749 and R² was 0.988. In the HQSAR, Q² was 0.84 and R² was 0.946. Visualization of these models was performed by contour maps showing favorable and unfavorable regions for activity, while visualization of HQSAR model was performed by a colored atomic contribution graph. Based on the results obtained of external validation, the CoMSIA model was statistically more significant and robust and was selected as the best model to predict new, more active inhibitors. To study the modes of interactions of the predicted compounds in the active site of MMP-2 and MMP-9, a simulation of molecular docking was realized. A combined study of MD simulations and calculation of free binding energy, were also carried out to validate the results obtained on the best predicted and most active compound in dataset and the compound NNGH as control compound. The results confirm the molecular docking results and indicate that the predicted ligands were stable in the binding site of MMP-2 and MMP-9.

Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques.

A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA (Q2 = 0.689; R = 0.999; R2pred = 0.986), CoMSIA (Q2 = 0.614; R2 = 0.923; R2pred = 0.815) and HQSAR (Q2= 0.603; R2 = 0.662; R2pred = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC50 inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma.

In silico identification of 1,2,4-triazoles as potential Candida Albicans inhibitors using 3D-QSAR, molecular docking, molecular dynamics simulations, and ADMET profiling.

Fluconazole and Voriconazole are individual antifungal inhibitors broadly adopted for treating fungal infections, including Candida Albicans. Unfortunately, these medicines clinically used have significant side effects. Consequently, the improvement of safer and better therapy became more indispensable. In this study, a set of 27 1,2,4-triazole compounds have been tested as potential Candida Albicans inhibitors by using different theoretical methods. The created comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour maps significantly impacted the development of novel Candida Albicans inhibitors with valuable activities. The mode of interactions between the 1,2,4-triazole inhibitors and the targeted receptor was studied by molecular docking simulation. The proposed new molecule P1 showed satisfied stability in the active pocket of the targeted receptor compared to the more active molecule in the dataset compared to Fluconazole medication. Meanwhile, the binding energy obtained by molecular docking for molecule P1 is - 9.3 kcal/mol compared with - 6.7 kcal/mol for Fluconazole medication. Also, MM/GBSA value obtained by molecular dynamics simulations at 100 ns for molecule P1 is - 33.34 kcal/mol compared with - 15.85 kcal/mol for Fluconazole medication. In addition, molecule P1 showed good oral bioavailability and was non-toxic according to ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the results indicated compound P1 might be a future inhibitor of Candida Albicans infection.

Novel Eubacterium rectale inhibitor from Coriandrum sativum L. for possible prevention of colorectal cancer: a computational approach.

This research aims to screen out the effective bioactive compounds from Coriander (Coriandrum sativum L.), which may be novel potential inhibitors of Eubacterium rectale for the prevention of colorectal cancer (CRC). A series of 8 coriander-derived chemical compounds previously assessed for their anti-inflammatory, antioxidant, and antidiabetic activities were tested against Carbohydrate ABC transporter substrate-binding protein and compared to the standard inhibitor Acarbose, to support their use as novel Eubacterium rectale inhibitors. Herein, these derivatives were submitted to a thorough analysis of docking studies, in which detailed interactions of the selected phytocompounds with carbohydrate ABC transporter substrate-binding protein were revealed. Molecular docking analysis recommends Rutin, Gallocatechin, and Epigallocatechin as the most potential Eubacterium rectale inhibitors among the eight selected phytochemical compounds. Subsequently, the stability of the three selected phytochemical complexes was checked using molecular dynamics (MD) simulation at 100 ns and Molecular Mechanics combined with Poisson-Boltzmann Surface Area (MM-PBSA). The results show quite good stability for Rutin and Gallocatechin. In silico ADMET prediction was performed on the selected compounds, and the findings revealed a reasonably good ADMET profile for both Rutin and Gallocatechin. The current findings predict that Gallocatechin could be a better CRC preventive natural compound, and, further in vitro, in vivo and clinical studies may confirm its therapeutic potential.Communicated by Ramaswamy H. Sarma.

High-throughput virtual screening approach of natural compounds as target inhibitors of plasmepsin-II.

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium falciparum parasite responsible for malaria, a disease that is causing deaths on a worldwide scale. Recently, plasmepsin II enzyme has gained much importance as an attractive drug target for the investigation of antimalarial drugs. In this sense, structure-based virtual screening have been utilized as tools in the process of discovering novel natural compounds based on quinoline as potential plasmepsin II inhibitors. Among the 58 quinoline derivatives isolated from different plants was screened by utilizing docking molecular, ADMET approaches, molecular dynamics simulation and MM-PBSA binding free energy. The first step in this work is building the 3 D structures of the plasmepsin II enzyme by using the SWISS-MODEL software. The optimized structures were subjected to virtual screening by Autodock Vina, an entity implicated in PyRx software. 21 were selected based on their binding affinity. The binding modes and interactions of the top-21 selected compounds were evaluated using AutoDock 4.2. Then, the pharmacokinetic proprieties and toxicity of these compounds were evaluated using ADMET analysis. Ten compounds were predicted to have ADMET characteristics with no side effects. Compounds M49 and M53 were found to be potential inhibitors. The stability of the selected two compounds was confirmed by MD simulation and MM/PBSA calculation during 200 ns. This study can be used to predict and to design new antimalarial drugs.Communicated by Ramaswamy H. Sarma.

A computational predicting of possible inhibitors of the main SARS-CoV-2 protease found in Algerian herbal medicines

COVID-19 is a zoonotic viral disease caused by the SARS-CoV-2 virus. Its abrupt outbreak has caused a tremendous challenge to public health systems due to the rapid spread of the virus. In this sense, a great deal of work has been focused on finding substances from herbal plants to be used against this virus. In order to investigate the molecular interactions between natural metabolites from Algerian herbal plants and the SARS-CoV-2 protease Mpro, computational docking and molecular dynamics were used, also the drug likeness degree and in silico ADMET prediction were carried out in this study. warfarin and catalponol preferentially binds to a pocket of the SARS-Cov-2 Mpro active site that is made up of residues His 41 to Glu 166 and Leu 27 to His 163 with a relatively low binding energy of -7.1 and -6.6 kcal/mol respectively. Dynamic molecular assay further established that only warfarin managed to stay in the active site. The results suggest that warfarin may be an interesting candidate for development as a medical treatment of COVID-19 and more research is proposed, without disregarding its toxicity which deserves to be well studied.

El COVID-19 es una enfermedad zoonótica causada por el virus SARS-CoV-2. Su abrupto brote en años recientes ha supuesto un tremendo desafío para los sistemas de salud pública, como resultado de la rápida propagación del virus. En tal sentido, muchos trabajos se han centrado en encontrar sustancias de origen vegetal, para ser utilizadas contra este virus. Se realizaron estudios de acoplamiento computacional y dinámica molecular para investigar las interacciones moleculares entre los metabolitos secundarios de las plantas herbales argelinas con la Proteasa Mpro del SARS-CoV-2, también se realizaron estudios de semejanza con drogas mediante ADMET computacional. La warfarina y el catalponol se unen preferentemente al sitio activo SARS-Cov-2 Mpro que se compone de residuos His 41 a Glu 166 y Leu 27 a His 163 con una energía de enlace relativamente baja, -7,1 y -6,6 kcal/mol respectivamente. Los ensayos de dinámica molecular establecieron además que sólo la warfarina logró permanecer en el sitio activo. Estos resultados sugieren que la warfarina puede ser un candidato interesante para el desarrollo como tratamiento médico de COVID-19 e instan a realizar más investigaciones, sin dejar de lado estudios de toxicidad respectivos.

A COVID-19 é uma doença zoonótica causada pelo vírus SARS-CoV-2, cujo surto abrupto nos últimos anos representou um tremendo desafio para os sistemas de saúde pública devido à rápida disseminação do vírus. Nesse sentido, muitos trabalhos têm se concentrado em encontrar substâncias de origem vegetal, para serem utilizadas contra esse vírus. Estudos de ancoragem computacional e dinâmica molecular foram conduzidos para investigar as interações moleculares entre metabólitos secundários de ervas argelinas com o SARS-CoV-2 Protease Mpro, estudos de similaridade de drogas também foram conduzidos usando ADMET in silico. A varfarina e o catalponol ligam-se preferencialmente ao sítio ativo SARS-Cov-2 Mpro que é composto pelos resíduos His 41 a Glu 166 e Leu 27 a His 163 com uma energia de ligação relativamente baixa, -7,1 e -6,6 kcal/mol, respectivamente. Ensaios de dinâmica molecular estabeleceram ainda que apenas a varfarina conseguiu permanecer no sítio ativo. Esses resultados sugerem que a varfarina pode ser um candidato interessante para desenvolvimento como tratamento médico para COVID-19 e exigem mais pesquisas, incluindo os respectivos estudos de toxicidade.

New organic dye-sensitized solar cells based on the D-A-π-A structure for efficient DSSCs: DFT/TD-DFT investigations.

Global energy consumption has increased due to population growth and economic development. Solar energy is one of the most important renewable energy sources for human consumption. In this research, four novel organic dyes (D2-D5) of the D-A-π-A structure based on triphenylamine (TPA) were studied theoretically using DFT and TD-DFT techniques for future usage as dye-sensitized solar cells (DSSCs). The effects of modifying the π-spacer of the reference molecule D1 on the structural, electronic, photovoltaic, and optical characteristics of the D2-D5 dyes were studied in detail. D2-D5 exhibited band gaps (E gap) in the range from 1.89 to 2.10 eV with λ abs in the range of 508 to 563 nm. The results obtained show that modifying the π-spacer of the dye D1 increased its hole injection and reinforced the intramolecular charge-transfer (ICT) impact, which resulted in a red-shifted ICT absorption with a greater molar extinction coefficient. The theoretically calculated open-circuit voltage (V oc) values ranged from 0.69 to 1.06 eV, while the light-harvesting efficiency (LHE) values varied from 0.95 to 0.99. Indeed, this theoretical research could guide chemists to synthesize effective dyes for DSSCs.

Computational approach investigation bioactive molecules from Saussurea Costus plant as SARS-CoV-2 main protease inhibitors using reverse docking, molecular dynamics simulation, and pharmacokinetic ADMET parameters.

SARS-COV-2 virus causes (COVID-19) disease; it has become a global pandemic since 2019 and has negatively affected all aspects of human life. Scientists have made great efforts to find a reliable cure, vaccine, or treatment for this emerging disease. Efforts have been directed towards using medicinal plants as alternative medicines, as the active chemical compounds in them have been discovered as potential antiviral or anti-inflammatory agents. In this research, the potential of Saussurea costus (S. Costus) or QUST Al Hindi chemical consistent as potential antiviral agents was investigated by using computational methods such as Reverse Docking, ADMET, and Molecular Dynamics with different proteases COVID-19 such as PDB: 2GZ9; 6LU7; 7AOL, 6Y2E, 6Y84. The results of Reverse Docking the complex between 6LU7 proteases and Cynaropicrin compound being the best complex, as the same result, is achieved by molecular dynamics. Also, the toxicity testing result from ADMET method proved that the complex is the least toxic and the safest possible drug. In addition, 6LU7-Cynaropicrin complex obeyed Lipinski rule; it formed ≤5 H-bond donors and ≤10 H bond acceptors, MW < 500 Daltons, and octanol/water partition coefficient <5.

Unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitors: Molecular docking, molecular dynamics, and ADME scoring investigations.

COVID-19 pandemic caused by very severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) agent is an ongoing major global health concern. The disease has caused more than 452 million affected cases and more than 6 million death worldwide. Hence, there is an urgency to search for possible medications and drug treatments. There are no approved drugs available to treat COVID-19 yet, although several vaccine candidates are already available and some of them are listed for emergency use by the world health organization (WHO). Identifying a potential drug candidate may make a significant contribution to control the expansion of COVID-19. The in vitro biological activity of asymmetric disulfides against coronavirus through the inhibition of SARS-CoV-2 main protease (Mpro) protein was reported. Due to the lack of convincing evidence those asymmetric disulfides have favorable pharmacological properties for the clinical treatment of Coronavirus, in silico evaluation should be performed to assess the potential of these compounds to inhibit the SARS-CoV-2 Mpro. In this context, we report herein the molecular docking for a series of 40 unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitor. The optimal binding features of disulfides within the binding pocket of SARS-CoV-2 endoribonuclease protein (Protein Data Bank [PDB]: 6LU7) was described. Studied compounds were ranked for potential effectiveness, and those have shown high molecular docking scores were proposed as novel drug candidates against SARS-CoV-2. Moreover, the outcomes of drug similarity and ADME (Absorption, Distribution, Metabolism, and Excretion) analyses have may have the effectiveness of acting as medicines, and would be of interest as promising starting point for designing compounds against SARS-CoV-2. Finally, the stability of these three compounds in the complex with Mpro was validated through molecular dynamics (MD) simulation, in which they displayed stable trajectory and molecular properties with a consistent interaction profile.

In silico investigation of phytoconstituents from Cameroonian medicinal plants towards COVID-19 treatment.

In silico studies performed on the metabolites of four Cameroonian medicinal plants with a view to propose potential molecules to fight against COVID-19 were carried out. At first, molecular docking was performed for a set of 84 selected phytochemicals with SARS-CoV-2 main protease (PDB ID: 6lu7) protein. It was further followed by assessing the pharmacokinetics and pharmacological abilities of 15 compounds, which showed low binding energy values. As the screening criteria for their ADMET properties were performed, only two compounds have shown suitable pharmacological properties for human administration which were shortlisted. Furthermore, the stability of binding of these compounds was assessed by performing molecular dynamics (MD) simulations. Based on further analysis through molecular dynamics simulations and reactivity studies, it was concluded that only the Pycnanthuquinone C (17) and the Pycnanthuquinone A (18) extracted from the Pycnanthus angolensis could be considered as candidate inhibitors for targeted protein. Indeed, we expect that these compounds could show excellent in vitro and in vivo activity against SARS-CoV-2. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01939-7.

Molecular docking, molecular dynamics simulation, and ADMET analysis of levamisole derivatives against the SARS-CoV-2 main protease (MPro).

Introduction: The new species of coronaviruses (CoVs), SARS-CoV-2, was reported as responsible for an outbreak of respiratory disease. Scientists and researchers are endeavoring to develop new approaches for the effective treatment against of the COVID-19 disease. There are no finally targeted antiviral agents able to inhibit the SARS-CoV-2 at present. Therefore, it is of interest to investigate the potential uses of levamisole derivatives, which are reported to be antiviral agents targeting the influenza virus. Methods: In the present study, 12 selected levamisole derivatives containing imidazo[2,1-b]thiazole were subjected to molecular docking in order to explore the binding mechanisms between these derivatives and the SARS-CoV-2 Mpro (PDB: 7BQY). The levamisole derivatives were evaluated for in silico ADMET properties for wet-lab applicability. Further, the stability of the best-docked complex was checked using molecular dynamics (MD) simulation at 20 ns. Results: Levamisole derivatives and especially molecule N°6 showed more promising docking results, presenting favorable binding interactions as well as better docking energy compared to chloroquine and mefloquine. The results of ADMET prediction and MD simulation support the potential of the molecule N°6 to be further developed as a novel inhibitor able to stop the newly emerged SARS-CoV-2. Conclusion: This research provided an effective first line in the rapid discovery of drug leads against the novel CoV (SARS-CoV-2).