GEORGE 1. BIRNBAUM, MIROSLAW CYCLER, and DAVID SHUGAR. Can. J . Chem. 62, 2646Chem. 62, (1984. Crystals of acyclovir belong to the space group P2,/n, and the cell dimensions are a = 25.459(1), b = 11.282 (I), c = 10.768(1) A, P = 95.16(1)". Intensity data were measured on a diffractometer and the structure was determined by direct methods. The asymmetric unit was found to contain three independent molecules of acyclovir and two molecules of water. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.053 for 3970 observed reflections. In two of the molecules the side chain is partially folded, while in the third one it is fully extended. The glycosidic torsion angles are in the range 91.4-104.3". The conformational features are compared with those in other known acyclonucleosides. They are also examined in relation to the behavior of acyclonucleosides and acyclonucleotides in various enzymatic systems, including those related to antiviral activities. (1) that replacement of the ribose moiety of guanosine by an acyclic chain corresponding to the "upper" portion of the ribose ring led to an analogue, 9-[(2-hydroxyethoxy)methyl]guanine (acycloG, acyclovir, ACV), with potent antiherpes activity. Interest in this compound, now licensed for clinical use, was further enhanced by the finding that, in HSV-infected cells, its mechanism of action was due to its specific phosphorylation by the viral-encoded (but not cellular) thymidine kinase to acyclo-GMP (l), followed by further phosphorylation by cellular GMP and GDP kinases to the triphosphate, acycloGTP, which is a selective and potent inhibitor of the HSV DNA polymerase (2).