Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.

Chronic hepatitis B virus (HBV) infection can result in severe liver disease with eventual progression to cirrhosis and hepatocellular carcinoma. 1 Roughly 5% of the world' s population (over 350 million persons) are chronically infected with HBV. 2 Although interferon alfa remains the only licensed drug for the treatment of chronic HBV infection, the overall response rate to this immunotherapy is less than 40%. 3 Therefore, other effective antiviral therapies for patients with HBV infection are needed.Lamivudine [(-)2Ј-deoxy-3Ј-thiacytidine, 3TC] is a member of a class of antiviral nucleoside analogs that inhibit hepadnavirus replication specifically by terminating viral DNA synthesis. 4 Lamivudine is currently being evaluated in Phase III clinical trials for the treatment of both patients chronically infected with HBV and patients with HBV reinfection of an allograft after orthotopic liver transplantation.In Phase II trials, 5-7 lamivudine treatment was shown to rapidly reduce serum HBV DNA to levels below the detection limit of standard commercial assays, and to be well tolerated with no major toxicities. However, as with other antivirals, 7-11 resistance to lamivudine therapy can emerge in some patients. Recent investigations have reported the development of lamivudine-resistant HBV in six orthotopic liver transplantation patients on therapy. [12][13][14] In each patient, sequence analysis of serum HBV DNA revealed the presence of specific mutations in the tyrosine, methionine, aspartate, aspartate (YMDD) amino acid motif of the viral polymerase. This YMDD motif is a conserved domain of all reverse transcriptases (RT) and is required for polymerization activity. However, various other amino acid changes in the polymerase were also described in these reports.To determine the significance of various mutations in the development of lamivudine-resistant HBV, a more comprehensive study was undertaken. In this study, DNA sequences were determined from HBV isolates from 20 patients experiencing breakthrough HBV reactivation while on lamivudine therapy. From this larger series of 20 clinical HBV isolates, the database of lamivudine-resistant HBV sequences was expanded to confirm viral DNA mutations associated with lamivudine resistance in vivo. To explore the biological significance of the key observed mutations, putative resis-

SUMMARY While the search for an efficacious HIV-1 vaccine remains elusive, emergence of a new generation of virus-neutralizing monoclonal antibodies (mAbs) has re-ignited the field of passive immunization for HIV-1 prevention. However, the plasticity of HIV-1 demands additional improvements to these mAbs to better ensure their clinical utility. Here, we report engineered bispecific antibodies that are the most potent and broad HIV-neutralizing antibodies to date. One bispecific antibody, 10E8V2.0/iMab, neutralized 118 HIV-1 pseudotyped viruses tested with a mean 50% inhibitory concentration (IC50) of 0.002 µg/mL. 10E8V2.0/iMab also potently neutralized 99% of viruses in a second panel of 200 HIV-1 isolates belonging to clade C, the dominant subtype accounting for ~50% of new infections worldwide. Importantly, 10E8V2.0/iMab reduced virus load substantially in HIV-1-infected humanized mice, and also provided complete protection when administered prior to virus challenge. These bispecific antibodies hold promise as novel prophylactic and/or therapeutic agents in the fight against HIV-1.