Vol. 7, Issue 11, Part B (2025)

SARS-CoV-2 main protease (Mpro / 3CLpro) is an essential viral enzyme responsible for polyprotein processing and maturation of the replication complex. Its strict preference for a Leu-Gln↓(Ser/Ala/Gly) motif and lack of close human homologs make it a high-selectivity antiviral target. Following early release of high-resolution crystal structures, global discovery programs rapidly applied structure-based design, converging on three non-negotiable interaction principles: (i) a P1 glutamine surrogate anchoring the S1 pocket, (ii) hydrophobic P2 bulk occupying S2, and (iii) tunable P3/P4 groups to balance solubility and pharmacokinetics. This mini-review summarizes the major chemotype classes advanced in 2020-2022: peptidomimetic aldehydes (11a/11b), ketoamides (13b), repurposed covalent inhibitors (N3, GC-376, boceprevir), nitrile-based reversible covalent inhibitors culminating in nirmatrelvir (Paxlovid), and emerging non-peptidyl scaffolds and metal complexes. We highlight design rules that consistently produced potent leads and caution against scaffolds that showed biochemical activity but failed under reducing or orthogonal validation assays. Collectively, these efforts illustrate how structural biology and computer-aided drug design accelerated the transition from concept to a clinically approved oral antiviral.