Viral polymerase and modulation thereof

A computer-assisted method to identify a potential HBV DNA polymerase antagonist comprising the steps of:

• (a) inputting into a progammed computer data comprising atomic co-ordinates of a wild-type HBV polymerase of genotype D as set forth in Table 6;
• (b) identifying a spatially adjacent amino acid in a variant HBV DNA polymerase, wherein the variant is a mutation selected from the group consisting of:
• rtA21S, rtA38E, rtY54H, rtN76D, rtL91I, rtF122L, rtY124H, rtT128N, rtQ130P, rtT184G, rtM204V/I, rtS202I, rtH248N, rtY252L, rtS21A, rtN/S/T/I/V53D, rtY54H, rtS57P, rtL91I, rtS116P, rtL122F, rtF122L, rtN124H, rtY124H, rtH126R, rtY126Q, rtT128N, rtP130Q, rtD131N, rtV134D, rtY135C, rtY141Y/F, rtL145M, rtF151T/F, rtL180M, rtA181T, rtS202G, rtI204V, rtK212R, rtL217R, rtS219A, rtI235I/M, rtN236T, rtN238D, sP120T, sM125T, sS126T, sT127A, sT118R, sM133L/M, sM133T, sF134V, sS143S/T, sD144A, sG145A, sW172Stop, sI195M, sS207R, sY225Y/C, spacerL97I, spacerK115R, spacerH116L, spacerL128F, spacerS137G, spacerR139G, spacerF142S, rtA97V, rtH126R, rtS135Y, rtM204I, PreS1 N114D, PreS1 T15S, PreS2 F22L, PreS2 V39A, PreS2 P52L, sL89V, sT118A, sF161L, sE164D, sI195M, sI208T, PreS1 E86Q, PreS1 N91K, PreS2 P41H, sQ30K, sP120T, sL176V, sV194F, rtS21A, rtL122F, rtN124H, rtH126R, rtP13.0Q, rtD131N, rtY135C, rtN/S/T/I/V53D, rtY126Q, rtS202G, rtI204V, rtI235I/M, sM125T, sT127A, sT118R, sM133T, sF134V, sI195M, sS207R, sY225Y/C, rtG172E, rtG174C, rtP177L, rtL180V, rtT184S, sR160N, sE164D, sF170L, sL175L/S, sQ181E/G/Q, sC/W182Y/STOP, sW196L, sW196S, sW196STOP, sM198I, sW199S, sS204T, sY206N, sS210K, sS210R, sL216STOP, sY255F, rtL77L/F, rtL77L/M/V, rtL80I, rtL80V, rtH90N/H, rtS117S/Y, rt125DELrt128, rtQ125K, rtQ125N, rtY126Q, rtL128L/M, rtT128A, rtL132L/M, rtN134G, rtS137T, rtN139H, rtN139K, rtY141Y/STOP, rtV/G142L, rtL147L/W, rtK149R, rtG153E, rtR153Q, rtW153S, rtW153Q, rtF166L, rtI169L, rtF178F/L, rtI187L, rtI187I/V, rtV191I, rtV191V/I, rtN202S, rtS202S/C, rtS202G, rtS213T, rtV/G214E, rtS219A, rtS219P, rtN/Q238H, rtN/S/H238N/K, rtN/S/H/T238/T/A/S/L, rtR242R/K, rtR242R/S, rtN248H, rtI253A, s118-207, s117-120DEL, sI68I/M, sC69F/L, sL109I/L, sG112R, sS17T, sT118R, sK122R, sT123P, sT126S, sT131N, sN131T, sM133K/M, sM133I, sY/F134S, sC139C/G, sK141E, sD144E, sG145R, rtT128T/I, rtL82M, rtT135C, rtT150A, rtV163I, rtT184S, rtA200V, rtF202V, rtS213T, rtQ215H, rtS219A, rtA222T, rtI224S, rtL229M, rtL235I, rtN238S, rtS78T, rt116DEL122, rtI163V, rtL180V, rtE8A, rtV23I, rtD31D/G, rtY53D, rtV58V/I, rtA/S21T, rtV/I/N/S/T53D, rtV/I/N/S/T53Y, rtS/T/N/H/A54Y/H, PreS2 L11L/A, PreS2 R171, DEL PreS2 18-21, PreS2 T30A, PreS2 N54H, sT13T/A, PreS2 Q1V, PreS2 Q1M, rtH90D, rtL/F108L, rtL157L/M, rtA181V, rtV207I, rtP109S, rtN/H/A/S/Q238K, s181M, sP214Q, sF83S, sL173F, sW199L, sI126T, sK160R, sS174N, sA84V, sS210N, sC69STOP/C, sC76Y, si110V/I, sY134N, sW172STOP/W, K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/deletion;
• V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/deletion;
• Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• H901/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/deletion;
• P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/deletion;
• and V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• said variant exhibiting resistance to a DNA polymerase antagonist;
• (c) generating, using computer methods, a set of atomic co-ordinates of a structure that possesses stereochemical complementarity to the atomic co-ordinates defined in (a) or a subset thereof, thereby generating a criteria data set;
• (d) inputting, using the processor, the criteria data set to a computer database of chemical structures;
• (e) selecting from the database, using computer methods, chemical structures that are similar to the criteria data set;
• and
• (f) outputting the selected chemical structures that are similar to a portion of the criteria data set;
• wherein the chemical structures are putative antagonists of the HBV polymerases.

A computer or a software component thereof that produces a three-dimensional representation of a molecule or molecular complex, which comprises a three-dimensional representation of a homolog of the molecule or molecular complex, which comprises a three-dimensional representation of a homolog of the molecule or molecular complex, in which the homolog comprises a domain that has a root mean square deviation from the backbone atoms of the amino acids of not more than 1.5 Å, in which the computer comprises:

• (a) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein the data comprises the structure co-ordinates of an HBV polymerase of genotype D as set forth in Table 6;
• (b) identifying spatially adjacent amino acids in a variant HBV polymerase selected from the group consisting of:
• rtA21S, rtA38E, rtY54H, rtN76D, rtL91I, rtF122L, rtY124H, rtT128N, rtQ130P, rtT184G, rtM204V/I, rtS202I, rtH248N, rtY252L, rtS21A, rtN/S/T/I/V53D, rtY54H, rtS57P, rtL91I, rtS116P, rtL122F, rtF122L, rtN124H, rtY124H, rtH126R, rtY126Q, rtT128N, rtP130Q, rtD131N, rtV134D, rtY135C, rtY141Y/F, rtL145M, rtF151T/F, rtL180M, rtA181T, rtS202G, rtI204V, rtK212R, rtL217R, rtS219A, rtI235I/M, rtN236T, rtN238D, sP120T, sM125T, sS126T, sT127A, sT118R, sM133L/M, sM133T, sF134V, sS143S/T, sD144A, sG145A, sW172Stop, s1195M, sS207R, sY225Y/C, spacerL97I, spacerK115R, spacerH116L, spacerL128F, spacerS137G, spacerR139G, spacerF142S, rtA97V, rtH126R, rtS135Y, rtM204I, PreS1 N114D, PreS1 T115S, PreS2 F22L, PreS2 V39A, PreS2 P52L, sL89V, sT118A, sF161L, sE164D, sI195M, sI208T, PreS1 E86Q, PreS1 N91K, PreS2 P41H, sQ30K, sP120T, sL176V, sV194F, rtS21A, rtL122F, rtN124H, rtH126R, rtP130Q, rtD131N, rtY135C, rtN/S/T/I/V53D, rtY126Q, rtS202G, rtI204V, rtI235I/M, sM125T, sT127A, sT118R, sM133T, sF134V, sI195M, sS207R, sY225Y/C, rtG172E, rtG174C, rtP177L, rtL180V, rtT184S, sR160N, sE164D, sF170L, sL175L/S, sQ181E/G/Q, sC/W182Y/STOP, sW196L, sW196S, sW196STOP, sM198I, sW199S, sS204T, sY206N, sS210K, sS210R, sL216STOP, sY255F, rtL77L/F, rtL77L/M/V, rtL801, rtL80V, rtH90N/H, rtS117S/Y, rt125DELrt128, rtQ125K, rtQ125N, rtY126Q, rtL128L/M, rtT128A, rtL132L/M, rtN134G, rtS137T, rtN139H, rtN139K, rtY141Y/STOP, rtV/G142L, rtL147L/W, rtK149R, rtG153E, rtR153Q, rtW153S, rtW153Q, rtF166L, rtI169L, rtF178F/L, rtI187L, rtI187I/V, rtV191I, rtV191V/I, rtN202S, rtS202S/C, rtS202G, rtS213T, rtV/G214E, rtS219A, rtS219P, rtN/Q238H, rtN/S/H238N/K, rtN/S/H/T238/T/A/S/L, rtR242R/K, rtR242R/S, rtN248H, rtI253A, s118-207, s117-120DEL, sI68I/M, sC69F/L, sL109I/L, sG112R, sS17T, sT118R, sK122R, sT123P, sT126S, sT131N, sN131T, sM133K/M, sM133I, sY/F134S, sC139C/G, sK141E, sD144E, sG145R, rtT128T/I, rtL82M, rtT135C, rtT150A, rtV163I, rtT184S, rtA200V, rtF202V, rtS213T, rtQ215H, rtS219A, rtA222T, rtI224S, rtL229M, rtL235I, rtN238S, rtS78T, rt116DEL122, rtI163V, rtL180V, rtE8A, rtV23I, rtD31D/G, rtY53D, rtV58V/I, rtA/S21T, rtV/I/N/S/T53D, rtV/I/N/S/T53Y, rtS/T/N/H/A54Y/H, PreS2 L11L/A, PreS2 R171, DEL PreS2 18-21, PreS2 T30A, PreS2 N54H, sT13T/A, PreS2 Q1V, PreS2 Q1M, rtH90D, rtL/F108L, rtL157L/M, rtA181V, rtV207I, rtP109S, rtN/H/A/S/Q238K, s181M, sP214Q, sF83S, sL173F, sW199L, sI126T, sK160R, sS174N, sA84V, sS210N, sC69STOP/C, sC76Y, si110V/I, sY134N, sW172STOP/W, K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/deletion;
• V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/deletion;
• Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• H901/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/deletion;
• P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• T237W/Y/V/A/R/N/D/C/Q/E/G/H/mL/K/M/F/P/S/deletion;
• P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/mL/K/deletion;
• G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/deletion;
• and V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• said DNA polymerase exhibiting resistance to an antagonist;
• (c) a working memory for storing instructions for processing the machine-readable data;
• (d) a central-processing unit coupled to the working memory and to the machine-readable data storage medium for processing the machine-readable data into the three-dimensional representation;
• and
• (e) a display coupled to the central-processing unit for displaying the three-dimensional representation.

A computer or a software component thereof that determines the structure co-ordinates corresponding to a three-dimensional structure of a molecule or molecular complex comprising an HBV polymerase, said computer comprises:

• (a) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, in which the data comprises at least a portion of the structural co-ordinates of a wild-type HBV polymerase as defined in Table 6;
• (b) identifying spatially adjacent amino acid in a variant HBV polymerase ahving a mutation selected from the group consisting of:
• rtA21S, rtA38E, rtY54H, rtN76D, rtL91I, rtF122L, rtY124H, rtT128N, rtQ130P, rtT184G, rtM204V/I, rtS202I, rtH248N, rtY252L, rtS21A, rtN/S/T/I/V53D, rtY54H, rtS57P, rtL91I, rtS116P, rtL122F, rtF122L, rtN124H, rtY124H, rtH126R, rtY126Q, rtT128N, rtP130Q, rtD131N, rtV134D, rtY135C, rtY141Y/F, rtL145M, rtF151T/F, rtL180M, rtA181T, rtS202G, rtI204V, rtK212R, rtL217R, rtS219A, rtI235I/M, rtN236T, rtN238D, sP120T, sM125T, sS126T, sT127A, sT118R, sM133L/M, sM133T, sF134V, sS143S/T, sD144A, sG145A, sW172Stop, sI195M, sS207R, sY225Y/C, spacerL97I, spacerK115R, spacerH116L, spacerL128F, spacerS137G, spacerR139G, spacerF142S, rtA97V, rtH126R, rtS135Y, rtM204I, PreS1 N114D, PreS1 T115S, PreS2 F22L, PreS2 V39A, PreS2 P52L, sL89V, sT118A, sF161L, sE164D, sI195M, sI208T, PreS1 E86Q, PreS1 N91K, PreS2 P41H, sQ30K, sP120T, sL176V, sV194F, rtS21A, rtL122F, rtN124H, rtH126R, rtP130Q, rtD131N, rtY135C, rtN/S/T/I/V53D, rtY126Q, rtS202G, rtI204V, rtI235I/M, sM125T, sT127A, sT118R, sM133T, sF134V, sI195M, sS207R, sY225Y/C, rtG172E, rtG174C, rtP177L, rtL180V, rtT184S, sR160N, sE164D, sF170L, sL175L/S, sQ181E/G/Q, sC/W182Y/STOP, sW196L, sW196S, sW196STOP, sM198I, sW199S, sS204T, sY206N, sS210K, sS210R, sL216STOP, sY255F, rtL77L/F, rtL77L/M/V, rtL80I, rtL80V, rtH90N/H, rtS117S/Y, rt125DELrt128, rtQ125K, rtQ125N, rtY126Q, rtL128L/M, rtT128A, rtL132L/M, rtN134G, rtS137T, rtN139H, rtN139K, rtY141Y/STOP, rtV/G142L, rtL147L/W, rtK149R, rtG153E, rtR153Q, rtW153S, rtW153Q, rtF166L, rtI169L, rtF178F/L, rtI187L, rtI187I/V, rtV191I, rtV191V/I, rtN202S, rtS202S/C, rtS202G, rtS213T, rtV/G214E, rtS219A, rtS219P, rtN/Q238H, rtN/S/H238N/K, rtN/S/H/T238/T/A/S/L, rtR242R/K, rtR242R/S, rtN248H, rtI253A, s118-207, s117-120DEL, sI68I/M, sC69F/L, sL109I/L, sG112R, sS17T, sT118R, sK122R, sT123P, sT126S, sT131N, sN131T, sM133K/M, sM133I, sY/F134S, sC139C/G, sK141E, sD144E, sG145R, rtT128T/I, rtL82M, rtT135C, rtT150A, rtV163I, rtT184S, rtA200V, rtF202V, rtS213T, rtQ215H, rtS219A, rtA222T, rtI224S, rtL229M, rtL235I, rtN238S, rtS78T, rt116DEL122, rtI163V, rtL180V, rtE8A, rtV23I, rtD31D/G, rtY53D, rtV58V/I, rtA/S21T, rtV/I/N/S/T53D, rtV/I/N/S/T53Y, rtS/T/N/H/A54Y/H, PreS2 L11L/A, PreS2 R171, DEL PreS2 18-21, PreS2 T30A, PreS2 N54H, sT13T/A, PreS2 Q1V, PreS2 Q1M, rtH90D, rtL/F108L, rtL157L/M, rtA181V, rtV207I, rtP109S, rtN/H/A/S/Q238K, s181M, sP214Q, sF83S, sL173F, sW199L, sI126T, sK160R, sS174N, sA84V, sS210N, sC69STOP/C, sC76Y, si110V/I, sY134N, sW172STOP/W, K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/deletion;
• V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/deletion;
• Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• H901/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/deletion;
• P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/deletion;
• and V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• said variant DNA polymerase exhibiting resistance to an antagonist;
• (c) a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein the data comprises atomic co-ordinates of differences between the wild type and variant HBV DNA polymerase;
• (d) a working memory for storing instructions for processing the machine-readable data of (a) and (b) and (c);
• (e) a central-processing unit coupled to the working memory and to the machine-readable data storage medium of (a) and (b) for performing a transformation of the machine readable data of (a) and for processing the machine-readable data of (b) into structure co-ordinates;
• and
• (f) a display coupled to the central-processing unit for displaying the structure co-ordinates of the molecule or molecular complex.

A computer-assisted method to identify or design HBV DNA polymerase antagonists that bind to a domain of HBV polymerase comprising the steps of:

• (a) inputting into a progammed computer data comprising the atomic co-ordinates of a wild-type HBV polymerase as set forth in Table 6;
• (b) identifying a spatially adjacent amino acid from a variant HBV DNA polymerase selected from the group consisting of:
• 28-36, 39-45, 59-66, 69-70, 73-93, 167-184, 198-213, 230-241 and 245-257 and/or at position numbers 4-10, 24-27, 46-58, 67-68, 71-72, 94-120, 165-166, 185-197, 214-227, 242-244 and 258-266;
• said variant exhibiting resistance to an antagonist;
• (c) generating, using computer methods, a set of atomic co-ordinates of the variant thereby generating a criteria data set;
• (d) with a processor, screening a database of chemical strctures that meet the criteria data set;
• and
• (e) outputting the selected chemical structures that are similar to the criteria data set.

A method of identifying an agent capable of interacting with a variant DNA polymerase or from an HBV resistant to a DNA polymerase antagonist, the variant comprising a mutation selected from the group consisting of:

• rtA21S, rtA38E, rtY54H, rtN76D, rtL91I, rtF122L, rtY124H, rtT128N, rtQ130P, rtT184G, rtM204V/I, rtS202I, rtH248N, rtY252L, rtS21A, rtN/S/T/I/V53D, rtY54H, rtS57P, rtL91I, rtS116P, rtL122F, rtF122L, rtN124H, rtY124H, rtH126R, rtY126Q, rtT128N, rtP130Q, rtD131N, rtV134D, rtY135C, rtY141Y/F, rtL145M, rtF151T/F, rtL180M, rtA181T, rtS202G, rtI204V, rtK212R, rtL217R, rtS219A, rtI235I/M, rtN236T, rtN238D, sP120T, sM125T, sS126T, sT127A, sT118R, sM133L/M, sM133T, sF134V, sS143S/T, sD144A, sG145A, sW172Stop, sI195M, sS207R, sY225Y/C, spacerL97I, spacerK115R, spacerH116L, spacerL128F, spacerS137G, spacerR139G, spacerF142S, rtA97V, rtH126R, rtS135Y, rtM204I, PreS1 N114D, PreS1 T115S, PreS2 F22L, PreS2 V39A, PreS2 P52L, sL89V, sT118A, sF161L, sE164D, sI195M, sI208T, PreS1 E86Q, PreS1 N91K, PreS2 P41H, sQ30K, sP120T, sL176V, sV194F, rtS21A, rtL122F, rtN124H, rtH126R, rtP130Q, rtD131N, rtY135C, rtN/S/T/I/V53D, rtY126Q, rtS202G, rtI204V, rtI235I/M, sM125T, sT127A, sT118R, sM133T, sF134V, sI195M, sS207R, sY225Y/C, rtG172E, rtG174C, rtP177L, rtL180V, rtT184S, sR160N, sE164D, sF170L, sL175L/S, sQ181E/G/Q, sC/W182Y/STOP, sW196L, sW196S, sW196STOP, sM198I, sW199S, sS204T, sY206N, sS210K, sS210R, sL216STOP, sY255F, rtL77L/F, rtL77L/M/V, rtL80I, rtL80V, rtH90N/H, rtS117S/Y, rt125DELrt128, rtQ125K, rtQ125N, rtY126Q, rtL128L/M, rtT128A, rtL132L/M, rtN134G, rtS137T, rtN139H, rtN139K, rtY141Y/STOP, rtV/G142L, rtL147L/W, rtK149R, rtG153E, rtR153Q, rtW153S, rtW153Q, rtF166L, rtI169L, rtF178F/L, rtI187L, rtI187I/V, rtV191I, rtV191V/I, rtN202S, rtS202S/C, rtS202G, rtS213T, rtV/G214E, rtS219A, rtS219P, rtN/Q238H, rtN/S/H238N/K, rtN/S/H/T238/T/A/S/L, rtR242R/K, rtR242R/S, rtN248H, rtI253A, sI18-207, si17-120DEL, sI68I/M, sC69F/L, sL109I/L, sG112R, sS17T, sT118R, sK122R, sT123P, sT126S, sT131N, sN131T, sM133K/M, sM133I, sY/F134S, sC139C/G, sK141E, sD144E, sG145R, rtT128T/I, rtL82M, rtT135C, rtT150A, rtV163I, rtT184S, rtA200V, rtF202V, rtS213T, rtQ215H, rtS219A, rtA222T, rtI224S, rtL229M, rtL235I, rtN238S, rtS78T, rt116DEL122, rtI163V, rtL180V, rtE8A, rtV23I, rtD31D/G, rtY53D, rtV58V/I, rtA/S21T, rtV/I/N/S/T53D, rtV/I/N/S/T53Y, rtS/T/N/H/A54Y/H, PreS2 L11L/A, PreS2 R171, DEL PreS2 18-21, PreS2 T30A, PreS2 N54H, sT13T/A, PreS2 Q1V, PreS2 Q1M, rtH90D, rtL/F108L, rtL157L/M, rtA181V, rtV207I, rtP109S, rtN/H/A/S/Q238K, s181M, sP214Q, sF83S, sL173F, sW199L, sI126T, sK160R, sS174N, sA84V, sS210N, sC69STOP/C, sC76Y, s1110V/I, sY134N, sW172STOP/W, K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/deletion;
• V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/deletion;
• Y89V/A R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• H901/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/deletion;
• P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/deletion;
• Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/deletion;
• M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/deletion;
• P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/deletion;
• N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/deletion;
• S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/deletion;
• Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/deletion;
• K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/deletion;
• L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/deletion;
• N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/deletion;
• H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/deletion;
• F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/deletion;
• M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/deletion;
• G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/deletion;
• and V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/deletion;
• the method comprising:
• (a) mapping a mutation in the variant HBV polymerase to a wild-type HBV DNA polymerase as defined in atomic coordinates as set forth in Table 6;
• and
• (b) designing an agent to interact with an HBV DNA polymerase having a chainge in the coordinates.

A method for screening for an agent capable of binding to and/or inhibiting an BHV polymerase, the method comprising:

• identifying a compound that is capable of binding, associating with or otherwise interacting with a region of an HBV polymerase selected from the group consisting of:
• (i) rtE1, rtH12, rtH13, rtH160 and rtA162;
• (ii) rtC-9, rtH-6, rtH90, rtL93, rtH234;
• and
• (iii) rtH197, rtC198, rtH216 and rtC213
• wherein said region is a metal ion binding site.

A diagnostic agent comprising a molecule capable of binding, associating with or interacting with a region of an HBV DNA polymerase defined at or near amino acid residues selected from the group consisting of:

• (i) rtE1, rtH12, rtH13, rtH160 and rtA162;
• (ii) rtC-9, rtH-6, rtH90, rtL93, rtH234;
• and
• (iii) rtH197, rtC198, rtH216 and rtC213,
• wherein said region is a metal ion binding site.