RESUMO
In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has spawned a worldwide catastrophe and global emergency. Amidst several anti-viral targets of COVID-19, spike glycoprotein has been recognized as an essential target for the viral entry into the host cell. In the search of effective SARS CoV-2 inhibitors acting against spike glycoprotein, the virtual screening of 175,851 ligands from the 2020.1 Asinex BioDesign library has been performed using in silico tools like SiteMap analysis, pharmacophore-based screening, molecular docking using different levels of precision, such as high throughput virtual screening, standard precision and extra precision, followed by absorption, distribution, metabolism, excretion and toxicity analysis, and molecular dynamics (MD) simulation. Following a molecular docking study, seventeen molecules (with a docking score of less than - 6.0) were identified having the substantial interactions with the catalytic amino acid and nucleic acid residues of spike glycoprotein at the binding site. In investigations using MD simulations for 10 ns, the hit molecules (1 and 2) showed adequate compactness and uniqueness, as well as satisfactory stability. These computational research findings have offered a key starting point in the field of design and development of novel SARS CoV-2 entry inhibitors with appropriate drug likeliness.
Assuntos
Tratamento Farmacológico da COVID-19 , Ácidos Nucleicos , Aminoácidos , Antivirais/química , Antivirais/farmacologia , Glicoproteínas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2-22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.
RESUMO
Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.
RESUMO
OBJECTIVE: Human cytochrome p450 enzymes play an important role in the metabolism of various substances. The CYP2C subfamily consists of various important drug-metabolizing enzymes such as CYP2C9 and CYP2C19. The objectives of the study include the determination of the frequency of genetic variants (CYP2C9*2, CYP2C9*3, and CYP2C19*2) of selected enzymes using allele-specific polymerase chain reaction (ASPCR) and its comparison with Indian as well as global past frequencies. We also aimed to study the impact of genetic mutation on clopidogrel efficacy and compare the efficacies between patients with and without CYP2C19*2 genetic variant. METHODOLOGY: In this study, the prevalence of variants CYP2C19*2, CYP2C9*2, and CYP2C9*3, the most popular variants of the respective enzymes, was determined using the ASPCR method. The correlation between the CYP2C19*2 variant and the antiplatelet activity of clopidogrel was studied using platelet aggregation assay (PAA). RESULTS: The determined frequencies of CYP2C19*2, CYP2C9*2, and CYP2C9*3 are 46%, 9%, and 12%. These frequencies are indicative of homozygous as well as heterozygous mutations. Reduced clopidogrel efficacy was observed in patients with a heterozygous mutation of CYP2C19*2 variant. CONCLUSIONS: The observed frequencies are not significantly different from that observed in earlier reported studies conducted across India and the world. Antiplatelet activity, as measured using the PAA method, was significantly lesser in patients having the CYP2C19*2 variant. The therapy failure in these patients can lead to serious cardiovascular consequences, and we propose determining the presence of the CYP2C19*2 variant before initiation of clopidogrel therapy.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Humanos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C9/genética , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C19/genética , Prevalência , Genótipo , Inibidores da Agregação Plaquetária/uso terapêuticoRESUMO
Being attracted with their cardiotonic, antidiabetic, cough relieving activity, treatment of fever, absorbent, anti-asthmatic, etc. activities reported in ancient Ayurvedic literature, phytochemicals of Onosma bracteata wall should be evaluated for their activity against SARS-CoV-2 virus. The main objective of this study is to identify a hit molecule for the inhibition of entry, replication, and protein synthesis of SARS CoV-2 virus into the host. To achieve given objective, computational virtual screening of phytochemicals of Onosma bracteata wall has been performed against three main viral targets: spike, RdRp, and Mpro. Further, the analysis of Lipinski's Ro5 and their estimation of ADMET profiles were performed using computational tools. The MD simulations studies of top hits against each viral target have also been performed for 20 ns to ensure their stability. The analysis of results revealed that Pulmonarioside C (9) and other plant compounds showed better binding affinity towards targets than existing antiviral compounds, making them probable lead compounds against SARS-CoV-2. Structural modifications and studies through in silico analysis provided the founding stone for the establishment of SARS CoV-2 inhibitory potential of phytoconstitutents of Onosma bracteata wall.
RESUMO
Due to alarming outbreak of pandemic COVID-19 in recent times, there is a strong need to discover and identify new antiviral agents acting against SARS CoV-2. Among natural products, lignan derivatives have been found effective against several viral strains including SARS CoV-2. Total of twenty-seven reported antiviral lignan derivatives of plant origin have been selected for computational studies to identify the potent inhibitors of SARS CoV-2. Molecular docking study has been carried out in order to predict and describe molecular interaction between active site of enzyme and lignan derivatives. Out of identified hits, clemastatin B and erythro-strebluslignanol G demonstrated stronger binding and high affinity with all selected proteins. Molecular dynamics simulation studies of clemastin B and savinin against promising targets of SARS CoV-2 have revealed their inhibitory potential against SARS CoV-2. In fine, in-silico computational studies have provided initial breakthrough in design and discovery of potential SARS CoV-2 inhibitors.