Fig. 2: Visualization of SARS-CoV-2 circulating variants relative to druggable pockets.

a, The gene encoding the main proteinase is neutral to the introduction of missense variants, with an overall missense tolerance score (MTR) and residual variation intolerance score (RVIS) both indicating that the gene is tolerant to genetic variation. Some circulating variants (red sticks) have already been observed to lead to alterations near binding sites of known inhibitors (boceprevir shown in yellow) and are likely to affect drug binding. Therefore, resistance mutations could be selected for with widespread use. b, The gene encoding helicase is among the SARS-CoV-2 genes most intolerant to missense variation, with low MTR and RVIS scores. Mapping the fragment-binding hotspots of the protein shows pockets with apolar (yellow), hydrogen-bond-donor (blue) and hydrogen-bond-acceptor (red) potential. Although some variation has been observed near this region, optimization of interactions to avoid these sites could decrease the potential for future resistance.