(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)thymine (DOT) is the first thymidine kinase-activated nucleoside that is significantly active against all of the clinically significant NRTI-resistant HIV-1 mutants, including AZT (D67N/K70R/T215Y/K219Q), Tenofovir (K65R), and Lamivudine (M184V). To understand the molecular mechanism of drug resistance and the antiviral activity of DOT against drug-resistant RTs, molecular modeling studies of DOT-TP complexed with the wild-type (WT) and mutated RT were conducted. The key reason for this interesting antiviral activity profile is the presence of a dioxolane ring.