Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2

被引:11
作者
Bastos, Ruan S. [1 ,2 ]
de Lima, Lucio R. [1 ,2 ]
Neto, Moyses F. A. [3 ]
Yousaf, Numan [4 ]
Cruz, Jorddy N. [2 ]
Campos, Joaquin M. [5 ,6 ]
Kimani, Njogu M. [7 ]
Ramos, Ryan S. [2 ]
Santos, Cleydson B. R. [1 ,2 ]
机构
[1] Fed Univ Para, Grad Program Med Chem & Mol Modeling, BR-66075110 Belem, PA, Brazil
[2] Univ Fed Amapa, Dept Biol & Hlth Sci, Lab Modeling & Computat Chem, BR-68903419 Macapa, AP, Brazil
[3] Univ Estadual Feira de Santana, Lab Mol Modeling, BR-44036900 Feira De Santana, BA, Brazil
[4] COMSATS Univ Islamabad, Dept Biosci, Pk Rd, Islamabad 45550, Pakistan
[5] Univ Granada, Fac Pharm, Dept Pharmaceut & Organ Chem, Campus Cartuja, Granada 18071, Spain
[6] Univ Granada, Biosanit Inst Granada ibs GRANADA, Granada 18071, Spain
[7] Univ Embu, Dept Phys Sci, Embu 6, Embu 60100, Kenya
关键词
COVID-19; new drugs; molecular modeling; antiviral; ESSENTIAL OILS; LIGAND; DATABASE; DRUGS;
D O I
10.3390/ijms24108814
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
When an epidemic started in the Chinese city ofWuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts' angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein's crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport((R)). The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of 8.645 kcal center dot mol(-1), which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC50 values (ranging from 0.459 to 2.371 mu M) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.
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页数:35
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