Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

Abstract

Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• non-structural protein 1
• molecular dynamics simulation
• drug design
• computational biology
• molecular modeling
• virtual screening

Acknowledgements

This work, performed at Universidade Federal de Goiás, was supported by the Ministério da Ciência e Tecnologia/Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI/CNPq), Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Additionally, G.L.M. were supported by fellowships from CAPES.

Author contributions

Protocol designed by: GLM; RAS

Monitoring the execution of work: RAS;

Methodology performed by: GLM; RAS

Manuscript was written and reviewed by: GLM; RAS

Disclosure statement

The authors declare no competing interests.

Table 1. Sixteen in common drugs among replicas as potential nsp1 inhibitors from Drugbank database.