# Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics
## 1 The COVID-19 Pandemic
### Potential Targets of Interest
Furthermore, it has recently been suggested that it could encompass also a third, essential function for the viral replication cycle, based on the fact that SARS-CoV-2 ExoN knockout mutants are nonviable despite the 95% sequence identity with SARS-CoV [227] and the conservation of important active site amino acids including both the cap-binding residues (N306, C309, R310, W385, N386, N422, and F426) and the S-adenosyl methionine (SAM) binding residues (D352, Q354, F367, Y368, and W385) [228,229]. After its cleavage by the M\({}^{\text{pro}}\), evidence suggests that it forms a binary complex with nsp10, which cooperatively exerts the proofreading activity on fresh RNAs produced by the RdRp machinery [230,231]. Although the binary complex theory is the most prominent one, an alternative hypothesis based on the formation of a ternary nsp10-nsp14-nsp16 has been proposed due to the flexibility of the lid subdomain of nsp14 and the fact that nsp10 also forms a heterocomplex with nsp16 [231]. Particularly, the nsp16-nsp10 heterodimer is responsible for the 2\({}^{\prime}\) O-methyltransferaseraserase activity that is required to complete the cap-0 \(\rightarrow\) cap-1 conversion of mRNA that is initiated by nsp14 [225]. While the catalytic activity entirely resides on nsp16, nsp10 provides a support role, aiding the recruitment of both the m7 GppA-RNA substrate (which happens at a binding site defined by residues K24, C25, L27, Y30, K46, Y132, K137, K170, T172, E173, H174, S201, and S202) and the SAM cofactor (which binds in a pocket defined by N43, G71, G73, G81, D99, D114, C115, D130, and M131), thus enhancing nsp16\({}^{\prime}\)s catalytic activity [232, 233, 234]. Lastly, another essential target for coronavirus biology is represented by nsp15, a uridine-specific endoribonuclease (NendoU) [235]. The active form of this enzyme is a dimer of trimers, with each monomer composed of 345 residues organized in three different domains: N-terminal, middle, and C-terminal NendoU, where the catalytic activity resides [236]. The active site contains six conserved residues: His250, His250, and Lys290, which compose the catalytic triad, and Thr341, Tyr343, and Ser294, with the latest associated with selectivity in substrate recognition [237]. Due to their localization within the hexamer, cooperativity or anticooperativity between different binding sites is possible [238]. Nsp15 enzymatic activity involves the cleavage of both single- and double-stranded RNA at uridine sites producing 2\({}^{\prime}\),3\({}^{\prime}\)-cyclic phosphodies, and 5\({}^{\prime}\)-hydroxyl termini [239]. Functionally speaking, Nsp15 seems to directly participate in viral replication through interference with the innate immune response [237]. Indeed, to evade host pattern recognition receptor MDA5 responsible for activating the host defenses, the Nsp15 cleaves the 5\({}^{\prime}\)-polyuridine tracts in (-) sense viral RNAs [240], though it has also been suggested that Nsp15 degrades viral RNA to hide it from the host defenses [238]. More detailed structural information about potentially druggable SARS-CoV-2 protein targets can be found in the works of [PERSON] et al. [241] and [PERSON] et al. [242].