Antibacterial, antifungal and antiviral activities of pyrimido[4,5- d]pyrimidine derivatives through computational approaches

Pyrimido[4,5-d]pyrimidine conveys antimicrobial activity against various micro pathogens having functionalized properties. As a result, this study has designed to illustrate the antibacterial, antifungal, and antiviral properties of pyrimido[4,5-d]pyrimidine. First of all, these structures have been optimized from the characterization of synthesis for calculating chemical descriptors by DFT. Next, the auto docking and target docking against 12 proteins, such as Pseudomonas aeruginosa (2Y0H), Bacillus cereus (1AH7), Escherichia coli (6DR3), Shigella dysenteriae (3FHH) Salmonella typhi (3FHU), Aspergillus niger (1ACZ), Aspergillus flavus (1XY3), Rhizomucor miehei (4WTP), Candida auris (6U8J), three proteins of SARS-CoV-2 (7T9J, 7T9L, and 7TB4) were performed for the determination of binding sites and binding affinity. One FDA approved drug (Ampicillin) has docked against 12 proteins while the Bacillus cereus (Bacteria), Aspergillus flavus (Fungus), and SARS-CoV-2, 7T9L (Omicron) are obtained the best binding affinity after docking. The most common residues are the PHE-66, ARG-176 and VAL-124 for Bacillus cereus, Aspergillus flavus and SARS-CoV-2, Omicron (7T9L), respectively, as they blocked the active sites by the ligands as inhibitors. It is revealed that this study contained both auto docking and target docking whereas the binding affinity of auto docking is that the binding affinity for auto docking is higher than target docking. Finally, among the nine compounds, three compounds show outstanding results against bacteria, fungus and virus. At last, molecular dynamics were performed to check the stability and validation of the docked complex and quantum calculations obtained the molecular properties, as well as ADMET, pharmacokinetics, Lipinski Rule and QSAR data.

Bilastine Based Drugs as SARS-CoV-2 Protease Inhibitors: Molecular Docking, Dynamics, and ADMET Related Studies

Bilastine drugs, structurally piperidine-1-carboxylate and sulfonyloxyethyl carboxylate derivatives, have significantly been employed as the medication of second-generation antihistamine drugs, and are used for the treatment of allergic rhinoconjunctivities and urticarial (hives). The bilastine drugs, composed of benzene carboxylate, propanoate, carboxylate, methyl-sulfonate, propanoic acid, butanoic acid, and pentanoic acid derivatives, were investigated through computational tools against SARS-CoV-2. The COVID-19 virus consists of five proteases where the curial function is performed by main proteases (M-pro) and Spike proteases (S-pro). The M-pro and S-pro were selected for calculation of molecular docking by these bilastine drugs which showed higher binding energy (<-6.5 kcal/mol) for both proteases. The main carboxylic acid group in bilastine drugs is found the primary key for a high binding score to show the large binding affinity with M-pro and S-pro, and is highly responsible for forming the hydrogen bond although the various hydrophobic bonds were produced as a weak interaction. For justification, the stability of molecular docked ligand-protein complexes was investigated with molecular dynamics. It showed that the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of all these drugs were below the 0.9 angstrom after residue interaction. Moreover, the HOMO-LUMO gap, hardness, and softness provided full details for their chemical reactivity. In this view, the pharmacokinetics and Lipinski rule were calculated, and all of these molecules had satisfied the Lipinski rule. Finally, using the admetSAR online database, absorption, distribution, metabolism, excretion, and toxicity have been calculated which indicated that these bilastine drugs are non-carcinogenic and less harmful for both aquatic and non-aquatic species. [GRAPHICS]

The Inhibitory Effect of Some Natural Bioactive D-Glucopyranoside Derivatives against SARS-CoV-2 Main Protease (Mpro) and Spike Protease (Spro)

Outbreak of coronavirus seems to have exacerbated across the globe, but drugs have not been discovered till now. Due to having the antiviral activity of D-glucopyranoside derivatives, this study was designed to examine as the inhibitor by in sillico study against the main protease (Mpro) and Spike protease (Spro) of SARS-CoV-2. First, these derivatives were optimised by Density Functional Theory (DFT). The observation of this study was monitored by molecular docking tools calculating the binding affinities. Afterwards, the ligand interaction with protein was accounted for selecting the how to bind of active sites of the protein. Next, the root means square deviation (RMSD) and root mean square fluctuation (RMSF) were illustrated for determining the stability of the docked complex. Finally, AMDET properties were calculated as well as the Lipisinki rule. All of the derivates showed a binding affinity more than -6.0 kcal/mol while derivatives 2, 3, and 9 were the best-bonded scoring inhibitor against Mpro and Spro. In addition, the chemical descriptors were more supportive tools as an inhibitor, and the Lipisinki rule was satisfied for maximum molecules as a drug. Besides, D-glucopyranoside derivatives may be predicted that they are non-carcinogenic and low toxic for both aquatic and non-aquatic species. © 2021. All Rights Reserved.

The computational screening of inhibitor for black fungus and white fungus by D-glucofuranose derivatives using in silico and SAR study

Black fungus is the foremost life-threatening disease during the SARS-CoV-2 affected patients and spreading quickly in the region of the subcontinent of India although there was no prescribed proper medication. As the Dglucofuranose and its derivatives are reported to show strong antifungal activity, this study has been designed with them for their computational investigation. Firstly, the overallprediction of activity spectra for substances (PASS) value illustrates a goodprobability to be active(Pa) and probability to be inactive (Pi) value. Next, pharmacokinetics parameters including drug-likeness and Lipinski's rules, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and overall quantum calculation of computational approaches by Density Functional Theory (DFT) have graduallybeen performed to analyze quantum calculations. After the analysis of docking score, it is found at -9.4 kcal/mol, -7.5 kcal/mol, -7.8 kcal/mol, -8.5 kcal/mol against the strain of black fungus protein strains Mycolicibacterium smegmatis, Mucor lusitanicus, Rhizomucor mieh, and white fungus protein Candida Auris, Aspergillus luchuensis and Candida albicans. Next, the molecular dynamics of docked complexes have been performed to check their stability in biological systems with water ranging 100 ns calculating the Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF)where the minimum RMSD and RMSF value indicated the higher stable configuration of docked complexes.These compounds have perfectly matched all the pharmacokinetics criteria to be a good drug candidate against both black and white fungus, and they are non-carcinogenic, low solubility, low toxic for both aquatic and non-aquatic. In addition, the quantum calculation using DFT conveys the strongest support and information about their chemical stability and biological significance. Finally, it could be concluded that the carboxylic group and methyl group inthe benzene ring causes higher binding affinity against black and white fungus protein strain through the formation of hydrogen and hydrophobic bonds. © 2021 ACG Publications All rights reserved

THE COMPUTATIONAL INVESTIGATION OF SIXTEEN ANTIVIRAL DRUGS AGAINST MAIN PROTEASE (MPRO) AND SPIKE PROTEASE (SPRO) OF SARS-CoV-2

In this research, the fourteen commonly used antiviral drugs were investigated through the computational tools against CoV-19 or SARS-2, as well as two small bioactive molecules from the cannabis plant, Tetrahydrocannabinol (THC) and Cannabinol (CBN). Thus, these were selelcted for molecular docking against main protein (5r7y) and spike protein (6xs6) of coronavirus. It was illustrated that the binding energies of Mpro for Pimodivir, Baloxavir Marboxil, Lopinavir, Baricitinib, Remdesivir, THC, Darunavir, Galidesivir, Nitazoxanide, CBN, Ritonavir, Penciclovir, Ribavirin, Favipiravir, Umifenovir, and Chloroquine were -8.6, -7.7, -7.6, -7.5, -7.3, -6.8, -6.6, -6.6, -6.6, -6.5, -6.5, -6.3, -6.2, -6.0, -5.7 and -5.4 kcal/mol, respectively, which could be supported for good binding molecules against micropathogens, where it was -9.8, -6.9, -6.9, -7.1, -7.1, -7.1, -7.5, -6.0, -6.2, -7.4, -5.8, -5.9, -5.7, -5.6 and -5.4 kcal/mol, respectively, for Spro. Among these, Pimodivir is a best-bonded molecule with Mpro and Spro in view of molecular docking score. Secondly, the ligand interaction was accounted for this protein against required corona virus protein consisting of weak H bonding, hydrophobic bond and Van dar Waal interaction. For justification of molecular docking, the molecular dynamics was calculated for top six scored drugs where the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were showed that the six drugs for both main protein and spike protein. Additionally, the chemical hardness and softness have calculated, and the lowest value of softness has found in sample 06 and 13 around 0.24. The HOMO-LUMO gap has calculated with a different value for all, but the lowest value has obtained for 01. Finally, the pharmacokinetics and Lipisinki rule were calculated, and all of these molecules had satisfied the Lipisinki rule. Finally, using the admetsar online data base, absorption, distribution, metabolism, excretion and toxicity have calculated. © 2021 Sociedad Chilena de Quimica. All rights reserved.

Modified D-Glucofuranoses as New Black Fungus Protease Inhibitors: Computational Screening, Docking, Dynamics, and QSAR Study

Notable antimicrobial functionality was found with different sugar esters which were also reported to inhibit the multidrug resistant pathogens along with promising antimicrobial efficacy, and drug-likeness properties. Recent black fungus outbreak, especially in India, along with COVID-19 surmounted the death toll and worsened the conditions severely due to lack of appropriate drugs. Hence, several glucofuranose type esters 4-8 were screened against black fungus related protein (2WTP). These molecules, optimized by DFT, showed good chemical and biological reactivity values especially with pathogens along with satisfactory ADMET profiles. With the good in vitro antifungal activities, these compounds were subjected for molecular docking against the protein of mucormycosis's pathogens, known as black fungus, followed by calculation of inhibition constant, binding energy, and molecular dynamics of the protein-ligand complex. Also, logpIC(50) or pIC(50) was calculated regarding the data for QSAR study. The molecular docking showed that 5-8 had a good binding affinity (> -6.50 kcal mol(-1)) while 7 (-8.00 kcal mol(-1)) and 8 (-8.20 kcal mol(-1)) possessed excellent binding affinity. The inhibition constant and binding energy of the compounds were found very lower among others with stable complexes in 5000 ns in molecular dynamics. Considering all the results, sugar esters 7 and 8 are found to have promising drug properties.