Dataset Information

Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein.

ABSTRACT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 S protein were analyzed. Tizoxanide, dolutegravir, bictegravir, and arbidol were found to have high binding energies, and they effectively bind key sites of the S1 and S2 subunits, inhibiting the virus by causing conformational changes in S1 and S2 during the fusion of the S protein with host cells. Based on the interactions among the drug molecules, the S protein and the amino acid environment around the binding sites, rational structure-based optimization was performed using the molecular connection method and bioisosterism strategy to obtain Ti-2, BD-2, and Ar-3, which have much stronger binding ability to the S protein than the original molecules. This study provides valuable clues for identifying S protein inhibitor binding sites and the mechanism of the anti-SARS-CoV-2 effect as well as useful inspiration and help for the discovery and optimization of small molecule S protein inhibitors.

SUBMITTER: Sun C

PROVIDER: S-EPMC7833228 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein.

Sun Chuancai C Zhang Jian J Wei Jiao J Zheng Xiaoli X Zhao Xianyang X Fang Zengjun Z Xu Dongmei D Yuan Huiqing H Liu Yipeng Y

PloS one 20210125 1

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 ...[more]

PMID: 33493227

Similar Datasets

Project description:Purpose Viral diseases increasingly endanger the world public health because of the transient efficacy of antiviral therapies. The novel coronavirus disease 2019 (COVID-19) has been recently identified as caused by a new type of coronaviruses. This type of coronavirus binds to the human receptor through the Spike glycoprotein (S) Receptor Binding Domain (RBD). The spike protein is found in inaccessible (closed) or accessible (open) conformations in which the accessible conformation causes severe infection. Thus, this receptor is a significant target for antiviral drug design. Methods An attempt was made to recognize 111 natural and synthesized compounds in order to utilize them against SARS-CoV-2 spike glycoprotein to inhibit Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using simulation methods, such as molecular docking. The FAF-Drugs3, Pan-Assay Interference Compounds (PAINS), ADME (absorption, distribution, metabolism, excretion) databases along with Lipinski’s rules were used to evaluate the drug-like properties of the identified ligands. In order to analyze and identify the residues critical in the docking process of the spike glycoprotein, the interactions of proposed ligands with both conformations of the spike glycoprotein was simulated. Results The results showed that among the available ligands, seven ligands had significant interactions with the binding site of the spike glycoprotein, in which angiotensin-converting enzyme 2 (ACE2) is bounded. Out of seven candidate molecules, six ligands exhibited drug-like characteristics. The results also demonstrated that fluorophenyl and propane groups of ligands had optimal interactions with the binding site of the spike glycoprotein. Conclusion According to the results, our findings indicated the ability of six ligands to prevent the binding of the SARS-CoV-2 spike glycoprotein to its cognate receptor, providing novel compounds for the treatment of COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s42600-020-00122-3.

Project description:COVID-19 is currently considered the ninth-deadliest pandemic, spreading through direct or indirect contact with infected individuals. It has imposed a consistent strain on both the financial and healthcare resources of many countries. To address this challenge, there is a pressing need for the development of new potential therapeutic agents for the treatment of this disease. To identify potential antiviral agents as novel dual inhibitors of SARS-CoV-2, we retrieved 404 alkaloids from 12 selected medicinal antiviral plants and virtually screened them against the renowned catalytic sites and favorable interacting residues of two essential proteins of SARS-CoV-2, namely, the main protease and spike glycoprotein. Based on docking scores, 12 metabolites with dual inhibitory potential were subjected to drug-likeness, bioactivity scores, and drug-like ability analyses. These analyses included the ligand-receptor stability and interactions at the potential active sites of target proteins, which were analyzed and confirmed through molecular dynamic simulations of the three lead metabolites. We also conducted a detailed binding free energy analysis of pivotal SARS-CoV-2 protein inhibitors using molecular mechanics techniques to reveal their interaction dynamics and stability. Overall, our results demonstrated that 12 alkaloids, namely, adouetine Y, evodiamide C, ergosine, hayatinine, (+)-homoaromoline, isatithioetherin C, N,alpha-L-rhamnopyranosyl vincosamide, pelosine, reserpine, toddalidimerine, toddayanis, and zanthocadinanine, are shortlisted as metabolites based on their interactions with target proteins. All 12 lead metabolites exhibited a higher unbound fraction and therefore greater distribution compared with the standards. Particularly, adouetine Y demonstrated high docking scores but exhibited a nonspontaneous binding profile. In contrast, ergosine and evodiamide C showed favorable binding interactions and superior stability in molecular dynamics simulations. Ergosine demonstrated exceptional performance in several key pharmaceutical metrics. Pharmacokinetic evaluations revealed that ergosine exhibited pronounced bioactivity, good absorption, and optimal bioavailability. Additionally, it was predicted not to cause skin sensitivity and was found to be non-hepatotoxic. Importantly, ergosine and evodiamide C emerged as superior drug candidates for dual inhibition of SARS-CoV-2 due to their strong binding affinity and drug-like ability, comparable to known inhibitors like N3 and molnupiravir. This study is limited by its in silico nature and demands the need for future in vitro and in vivo studies to confirm these findings.

Dataset Information

Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein.

Publications

Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets