# Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics
## 1 The COVID-19 Pandemic
### Rational Design of COVID-19 Drugs  
Several characteristics of the viral proteases family, including SARS-CoV-2 M\({}^{\rm pro}\), make them an attractive target for the rational development of tailored drugs against COVID-19. First, the low sequence identity with human proteases coupled with distinct cleavage-site specificities reduces the possibility of off-target/side effects associated with the therapy [168]. Second, the striking conservation of protein fold and structural organization of the active site among different members of the same family leads to the possibility of developing pan-coronaviral drugs [169]. Third, the abundance of structural data about the SARS-CoV-2 main protease (659 structures have been deposited in the Protein Data Bank [170] to date) makes it possible to exploit the state-of-the-art structure-based approaches in drug design [171]. Furthermore, a similar strategy has already proved successful in finding efficient treatments against the hepatitis C virus [172; 173] and human immunodeficiency virus (HIV) [174; 175]. Finally, the experience acquired studying the original SARS-CoV protease [176], in conjunction with the rapid release to the scientific community of the SARS-CoV-2 protease [164], certainly played a major role in determining its prominent place within most COVID-19 drug discovery campaigns. A detailed report on structural features of the 3 CL\({}^{\rm pro}\) protease that can guide the design of novel inhibitors can be found in the work of [PERSON] et al. [177]. The first attempts at finding SARS-CoV-2 M\({}^{\rm pro}\) inhibitors involved the repurposing of existing protease inhibitors. Particularly, the hepatitis C protease inhibitor Boceprevir [178; 179] and the feline coronavirus 3 CL\({}^{\rm pro}\) inhibitor GC373 (derived from its prodrug GC376) [180] were found to be active in the low uM potency range against M\({}^{\rm pro}\)[181], with the latter being particularly interesting due its promiscuous anticoronaviral activity [182]. Both candidate drugs share a similar peptidomimetic scaffold, which entails the most prominent interaction features of the first identified ones [164]. Although these primary hit compounds present a good binding pattern, their evolution towards clinical candidates and drugs is prevented by two main factors: first, covalent inhibitors are usually associated with selectivity problems, due to their ability to react promiscuously with a plethora of nucleophile moieties [183]; second, the peptidomimeticscaffold is usually associated with suboptimal pharmacokinetic properties that affect the preferred route of administration [184]. In this regard, a step forward was obtained when the first SARS-CoV-2 MP\({}^{\text{pro}}\) inhibitors were able to reach clinical stage experimentation, namely PF-07304814 (lately renamed as Lufotrelvir), a prodrug for the active principle PF-00835231, and PF-07321332 (Nirmatrelvir). Lufotrelvir was originally developed by Pfizer in 2002-2003 for the SARS-CoV virus and later repurposed against the SARS-CoV-2 due to the high similarities between the two proteases [185]. Due to its efficacy against several viral strains in preclinical studies [186; 187], it was advanced to the clinical stages of experimentation, albeit quickly overcome by Nirmatrelvir thanks to its more favorable pharmacokinetic profile [188]. Contrary to Lufotrelvir, which, similar to Remdesivir, requires parenteral administration, Nirmatrelvir can be administered orally [189], a must-have characteristic for the widespread adoption of drugs [190; 191]. Designed by Pfizer amid the pandemic through the rational modification of Lufotrelvir [192], the structure of Nirmatrelvir was officially presented to the general audience on 6 April at the American Chemical Society Spring 2021 meeting [193], only one year after the official start of its development process [192] (Figure 3).