In-silico molecular modelling studies of some camphor imine based compounds as anti-influenza A (H1N1) pdm09 virus agents.

The advent of influenza A (H1N1) drug-resistant strains led to the search quest for more potent inhibitors of the influenza A virus, especially in this devastating COVID-19 pandemic era. Hence, the present research utilized some molecular modelling strategies to unveil new camphor imine-based compounds as anti-influenza A (H1N1) pdm09 agents. The 2D-QSAR results revealed GFA-MLR (R2train = 0.9158, Q2=0.8475) and GFA-ANN (R2train = 0.9264, Q2=0.9238) models for the anti-influenza A (H1N1) pdm09 activity prediction which have passed the QSAR model acceptability thresholds. The results from the 3D-QSAR studies also revealed CoMFA (R2train =0.977, Q2=0.509) and CoMSIA_S (R2train =0.976, Q2=0.527) models for activity predictions. Based on the notable information derived from the 2D-QSAR, 3D-QSAR, and docking analysis, ten (10) new camphor imine-based compounds (22a-22j) were designed using the most active compound 22 as the template. Furthermore, the high predicted activity and binding scores of compound 22j were further justified by the high reactive sites shown in the electrostatic potential maps and other quantum chemical calculations. The MD simulation of 22j in the active site of the influenza hemagglutinin (HA) receptor confirmed the dynamic stability of the complex. Moreover, the appraisals of drug-likeness and ADMET properties of the proposed compounds showed zero violation of Lipinski's criteria with good pharmacokinetic profiles. Hence, the outcomes in this work recommend further in-depth in vivo and in-vitro investigations to validate these theoretical findings.Communicated by Ramaswamy H. Sarma.

Molecular modelling studies of substituted indole derivatives as novel influenza a virus inhibitors.

The emergence of drug-resistant strains motivate researchers to find new innovative anti-IAV candidates with a different mode of action. In this work, molecular modelling strategies, such as 2D-QSAR, 3D-QSAR, molecular docking, molecular dynamics, FMOs, and ADMET were applied to some substituted indoles as IAV inhibitors. The best-developed 2D-QSAR models, MLR (Q2 = 0.7634, R2train = 0.8666) and ANN[4-3-1] (Q2 = 0.8699, R2train = 0.8705) revealed good statistical validation for the inhibitory response predictions. The 3D-QSAR models, CoMFA (Q2 = 0.504, R2train = 0.805) and CoMSIA/SEDHA (Q2 = 0.619, R2train = 0.813) are selected as the best 3D models following the global thresholds. In addition, the contour maps generated from the CoMFA and CoMSIA models illustrate the relationship between the molecular fields and the inhibitory effects of the studied molecules. The results of the studies led to the design of five new molecules (24a-e) with enhanced anti-IAV activities and binding potentials using the most active molecule (24) as the template scaffold. The conformational stability of the best-designed molecules with the NA protein showed hydrophobic and H-bonds with the key residues from the molecular dynamics simulations of 100 ns. Furthermore, the global reactivity indices from the DFT calculations portrayed the relevance of 24c in view of its smaller band gap as also justified by our QSAR and molecular simulation studies.Communicated by Ramaswamy H. Sarma.

Retraction notice to "In-silico modelling studies of 5-benzyl-4-thiazolinone derivatives as influenza neuraminidase inhibitors via 2D-QSAR, 3D-QSAR, molecular docking, and ADMET predictions" [Heliyon 8, 2022 Article e10101].

[This retracts the article DOI: 10.1016/j.heliyon.2022.e10101.].

Combining docking, molecular dynamics simulations, AD-MET pharmacokinetics properties, and MMGBSA calculations to create specialized protocols for running effective virtual screening campaigns on the autoimmune disorder and SARS-CoV-2 main protease.

The development of novel medicines to treat autoimmune diseases and SARS-CoV-2 main protease (Mpro), a virus that can cause both acute and chronic illnesses, is an ongoing necessity for the global community. The primary objective of this research is to use CoMFA methods to evaluate the quantitative structure-activity relationship (QSAR) of a select group of chemicals concerning autoimmune illnesses. By performing a molecular docking analysis, we may verify previously observed tendencies and gain insight into how receptors and ligands interact. The results of the 3D QSAR models are quite satisfactory and give significant statistical results: Q_loo∧2 = 0.5548, Q_lto∧2 = 0.5278, R∧2 = 0.9990, F-test = 3,101.141, SDEC = 0.017 for the CoMFA FFDSEL, and Q_loo∧2 = 0.7033, Q_lto∧2 = 0.6827, Q_lmo∧2 = 0.6305, R∧2 = 0.9984, F-test = 1994.0374, SDEC = 0.0216 for CoMFA UVEPLS. The success of these two models in exceeding the external validation criteria used and adhering to the Tropsha and Glorbaikh criteria's upper and lower bounds can be noted. We report the docking simulation of the compounds as an inhibitor of the SARS-CoV-2 Mpro and an autoimmune disorder in this context. For a few chosen autoimmune disorder receptors (protein tyrosine phosphatase, nonreceptor type 22 (lymphoid) isoform 1 (PTPN22), type 1 diabetes, rheumatoid arthritis, and SARS-CoV-2 Mpro, the optimal binding characteristics of the compounds were described. According to their potential for effectiveness, the studied compounds were ranked, and those that demonstrated higher molecular docking scores than the reference drugs were suggested as potential new drug candidates for the treatment of autoimmune disease and SARS-CoV-2 Mpro. Additionally, the results of analyses of drug similarity, ADME (Absorption, Distribution, Metabolism, and Excretion), and toxicity were used to screen the best-docked compounds in which compound 4 scaled through. Finally, molecular dynamics (MD) simulation was used to verify compound 4's stability in the complex with the chosen autoimmune diseases and SARS-CoV-2 Mpro protein. This compound showed a steady trajectory and molecular characteristics with a predictable pattern of interactions. These findings suggest that compound 4 may hold potential as a therapy for autoimmune diseases and SARS-CoV-2 Mpro.

Structure-based drug design, molecular dynamics simulation, ADMET, and quantum chemical studies of some thiazolinones targeting influenza neuraminidase.

The genetic mutability of the influenza virus leads to the existence of drug-resistant strains which is dangerous, particularly with the lingering coronavirus disease (COVID-19). This necessitated the need for the search and discovery of more potential anti-influenza agents to avert future outbreaks. In furtherance of our previous in-silico studies on 5-benzyl-4-thiazolinones as anti-influenza neuraminidase (NA) inhibitors, molecule 11 was selected as the template scaffold for the structure-based drug design due to its good binding, pharmacokinetic profiling, and better NA inhibitory activity. As such, eighteen (18) new molecules (11a-r) were designed with better MolDock scores as compared with the template scaffold and the zanamivir reference drug. However, the dynamic stability of molecule 11a in the binding cavity of the NA target (3TI5) showed water-mediated hydrogen and hydrophobic bondings with the active residues such as Arg118, Ile149, Arg152, Ile222, Trp403, and Ile427 after the MD simulation for 100 ns. The drug-likeness and ADMET assessment of all designed molecules predicted non-violation of the stipulated thresholds of Lipinski's rule and good pharmacokinetic properties respectively. In addition, the quantum chemical calculations also suggested the significant chemical reactivity of molecules with their smaller band energy gap, high electrophilicity, high softness, and low hardness. The results obtained in this study proposed a reliable in-silico viewpoint for anti-influenza drug discovery and development.Communicated by Ramaswamy H. Sarma.

Computational modelling studies of some 1,3-thiazine derivatives as anti-influenza inhibitors targeting H1N1 neuraminidase via 2D-QSAR, 3D-QSAR, molecular docking, and ADMET predictions.

Background: Influenza virus disease remains one of the most contagious diseases that aided the deaths of many patients, especially in this COVID-19 pandemic era. Recent discoveries have shown that the high prevalence of influenza and SARS-CoV-2 coinfection can rapidly increase the death rate of patients. Hence, it became necessary to search for more potent inhibitors for influenza disease therapy. The present study utilized some computational modeling concepts such as 2D-QSAR, 3D-QSAR, molecular docking simulation, and ADMET predictions of some 1,3-thiazine derivatives as inhibitors of influenza neuraminidase (NA). Results: The 2D-QSAR modeling results showed GFA-MLR ( R train 2 = 0.9192, Q 2 = 0.8767, R 2 adj = 0.8991, RMSE = 0.0959, R test 2 = 0.8943, R pred 2 = 0.7745) and GFA-ANN ( R train 2 = 0.9227, Q 2 = 0.9212, RMSE = 0.0940, R test 2 = 0.8831, R pred 2 = 0.7763) models with the computed descriptors as ATS7s, SpMax5_Bhv, nHBint6, and TDB9m for predicting the NA inhibitory activities of compounds which have passed the global criteria of accepting QSAR model. The 3D-QSAR modeling was carried out based on the comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA). The CoMFA_ES ( R train 2 = 0.9620, Q 2 = 0.643) and CoMSIA_SED ( R train 2 = 0.8770, Q 2 = 0.702) models were found to also have good and reliable predicting ability. The compounds were also virtually screened based on their binding scores via molecular docking simulations with the active site of the NA (H1N1) target receptor which also confirms their resilient potency. Four potential lead compounds (4, 7, 14, and 15) with the relatively high inhibitory rate (> 50%) and docking (> - 6.3 kcal/mol) scores were identified as the possible lead candidates for in silico exploration of improved anti-influenza agents. Conclusion: The drug-likeness and ADMET predictions of the lead compounds revealed non-violation of Lipinski's rule and good pharmacokinetic profiles as important guidelines for rational drug design. Hence, the outcome of this research set a course for the in silico design and exploration of novel NA inhibitors with improved potency.

In-silico modelling studies of 5-benzyl-4-thiazolinone derivatives as influenza neuraminidase inhibitors via 2D-QSAR, 3D-QSAR, molecular docking, and ADMET predictions.

Influenza virus disease is one of the most infectious diseases responsible for many human deaths, and the high mutability of the virus causes drug resistance effects in recent times. As such, it became necessary to explore more inhibitors that could avert future influenza pandemics. The present research utilized some in-silico modelling concepts such as 2D-QSAR, 3D-QSAR, molecular docking simulation, and ADMET predictions on some 5-benzyl-4-thiazolinone derivatives as influenza neuraminidase (NA) inhibitors. The 2D-QSAR modelling results revealed GFA-MLR ( R train 2 =0.8414, Q2 = 0.7680) and GFA-ANN ( R train â€‹ 2 =0.8754, Q2 = 0.8753) models with the most relevant descriptors (MATS3i, SpMax5_Bhe, minsOH and VE3_D) for predicting the inhibitory activities of the molecules which has passed the global criteria of accepting QSAR models. The results of the 3D-QSAR modelling results showed that CoMFA_ES ( R train â€‹ 2 =0.9030, Q2 = 0.5390) and CoMSIA_EA ( R train 2 =0.880, Q2 = 0.547) models are having good predicting ability among other developed models. The molecules were virtually screened via molecular docking simulation with the active site of NA protein receptor (pH1N1) which confirms their resilient potency when compared with zanamivir standard drug. Molecule 11 as the most potent molecule formed more H-bond interactions with the key residues such as TRP178, ARG152, ARG292, ARG371, and TYR406 that triggered the catalytic reactions for NA inhibition. Furthermore, six (6) molecules (9, 10, 11, 17, 22, and 31) with relatively high inhibitory activities and docking scores were identified as the possible leads for in-silico exploration of novel NA inhibitors. The drug-likeness and ADMET predictions of the lead molecules revealed non-violation of Lipinski's rule and good pharmacokinetic profiles respectively, which are important guidelines for rational drug design. Hence, the outcome of this study overlaid a solid foundation for the in-silico design and exploration of novel NA inhibitors with improved potency.

QSAR, homology modeling, and docking simulation on SARS-CoV-2 and pseudomonas aeruginosa inhibitors, ADMET, and molecular dynamic simulations to find a possible oral lead candidate.

Background: In seek of potent and non-toxic iminoguanidine derivatives formerly assessed as active Pseudomonas aeruginosa inhibitors, a combined mathematical approach of quantitative structure-activity relationship (QSAR), homology modeling, docking simulation, ADMET, and molecular dynamics simulations were executed on iminoguanidine derivatives. Results: The QSAR method was employed to statistically analyze the structure-activity relationships (SAR) and had conceded good statistical significance for eminent predictive model; (GA-MLR: Q2 LOO = 0.8027; R 2 = 0.8735; R 2 ext = 0.7536). Thorough scrutiny of the predictive models disclosed that the Centered Broto-Moreau autocorrelation - lag 1/weighted by I-state and 3D topological distance-based autocorrelation-lag 9/weighted by I-state oversee the biological activity and rendered much useful information to realize the properties required to develop new potent Pseudomonas aeruginosa inhibitors. The next mathematical model work accomplished here emphasizes finding a potential drug that could aid in curing Pseudomonas aeruginosa and SARS-CoV-2 as the drug targets Pseudomonas aeruginosa. This involves homology modeling of RNA polymerase-binding transcription factor DksA and COVID-19 main protease receptors, docking simulations, and pharmacokinetic screening studies of hits compounds against the receptor to identify potential inhibitors that can serve to regulate the modeled enzymes. The modeled protein exhibits the most favorable regions more than 90% with a minimum disallowed region less than 5% and is simulated under a hydrophilic environment. The docking simulations of all the series to the binding pocket of the built protein model were done to demonstrate their binding style and to recognize critical interacting residues inside the binding site. Their binding constancy for the modeled receptors has been assessed through RMSD, RMSF, and SASA analysis from 1-ns molecular dynamics simulations (MDS) run. Conclusion: Our acknowledged drugs could be a proficient cure for SARS-CoV-2 and Pseudomonas aeruginosa drug discovery, having said that extra testing (in vitro and in vivo) is essential to explain their latent as novel drugs and manner of action. Supplementary Information: The online version contains supplementary material available at 10.1186/s43141-022-00362-z.