Systematic review on role of structure based drug design (SBDD) in the identification of anti-viral leads against SARS-Cov-2

Abstract

The outbreak of existing public health distress is threatening the entire world with emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel coronavirus disease 2019 (COVID-19) is mild in most people. However, in some elderly people with co-morbid conditions, it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction leading to death. COVID-19 has caused global panic in the healthcare sector and has become one of the biggest threats to the global economy. Drug discovery researchers are expected to contribute rapidly than ever before. The complete genome sequence of coronavirus had been reported barely a month after the identification of first patient. Potential drug targets to combat and treat the coronavirus infection have also been explored. The iterative structure-based drug design (SBDD) approach could significantly contribute towards the discovery of new drug like molecules for the treatment of COVID-19. The existing antivirals and experiences gained from SARS and MERS outbreaks may pave way for identification of potential drug molecules using the approach. SBDD has gained momentum as the essential tool for faster and costeffective lead discovery of antivirals in the past. The discovery of FDA approved human immunodeficiency virus type 1 (HIV-1) inhibitors represent the foremost success of SBDD. This systematic review provides an overview of the novel coronavirus, its pathology of replication, role of structure based drug design, available drug targets and recent advances in in-silico drug discovery for the prevention of COVID-19. SARSCoV- 2 main protease, RNA dependent RNA polymerase (RdRp) and spike (S) protein are the potential targets, which are currently explored for the drug development.

Keywords: Coronavirus 2; Proteases; RNA dependent RNA polymerase; Spike (S) protein; Structure based drug design.

Fig. 1

Workflow of structure-based drug design (SBDD) in the drug discovery process.

Fig. 2

Drugs developed through structure-based drug design.

Fig. 3

Life cycle of severe acute respiratory syndrome coronavirus (SARS-Covid-19) and its potential targets.

Fig. 4

Drugs being repurposed for COVID-19.

Fig. 5

Molecular interactions of compound N3 with SARS-CoV-2 Mpro (Protein Data Bank ID: 6LU7).

Fig. 6

The crystal structure of NSP12 polymerase bound with co-factor NSP7-NSP8 with a second subunit of NSP8 in complex with zinc atom (Protein Data Bank ID: 6NUR).