J Chem Inf Model - Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

Tópicos

{ compound(1573) activ(1297) structur(1058) }
{ bind(1733) structur(1185) ligand(1036) }
{ studi(2440) review(1878) systemat(933) }
{ perform(1367) use(1326) method(1137) }
{ activ(1138) subject(705) human(624) }
{ activ(1452) weight(1219) physic(1104) }
{ model(2220) cell(1177) simul(1124) }
{ featur(1941) imag(1645) propos(1176) }
{ system(1050) medic(1026) inform(1018) }
{ visual(1396) interact(850) tool(830) }
{ studi(1119) effect(1106) posit(819) }
{ medic(1828) order(1363) alert(1069) }
{ use(1733) differ(960) four(931) }
{ implement(1333) system(1263) develop(1122) }
{ imag(1057) registr(996) error(939) }
{ sequenc(1873) structur(1644) protein(1328) }
{ method(1219) similar(1157) match(930) }
{ imag(2675) segment(2577) method(1081) }
{ patient(2315) diseas(1263) diabet(1191) }
{ extract(1171) text(1153) clinic(932) }
{ general(901) number(790) one(736) }
{ howev(809) still(633) remain(590) }
{ research(1085) discuss(1038) issu(1018) }
{ spatial(1525) area(1432) region(1030) }
{ model(3480) simul(1196) paramet(876) }
{ monitor(1329) mobil(1314) devic(1160) }
{ group(2977) signific(1463) compar(1072) }
{ gene(2352) biolog(1181) express(1162) }
{ survey(1388) particip(1329) question(1065) }
{ decis(3086) make(1611) patient(1517) }
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{ control(1307) perform(991) simul(935) }
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{ method(984) reconstruct(947) comput(926) }
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{ studi(1410) differ(1259) use(1210) }
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{ record(1888) medic(1808) patient(1693) }
{ health(3367) inform(1360) care(1135) }
{ ehr(2073) health(1662) electron(1139) }
{ state(1844) use(1261) util(961) }
{ research(1218) medic(880) student(794) }
{ patient(2837) hospit(1953) medic(668) }
{ model(2656) set(1616) predict(1553) }
{ data(2317) use(1299) case(1017) }
{ age(1611) year(1155) adult(843) }
{ signal(2180) analysi(812) frequenc(800) }
{ cost(1906) reduc(1198) effect(832) }
{ sampl(1606) size(1419) use(1276) }
{ data(3008) multipl(1320) sourc(1022) }
{ first(2504) two(1366) second(1323) }
{ intervent(3218) particip(2042) group(1664) }
{ time(1939) patient(1703) rate(768) }
{ patient(1821) servic(1111) care(1106) }
{ use(2086) technolog(871) perceiv(783) }
{ can(981) present(881) function(850) }
{ analysi(2126) use(1163) compon(1037) }
{ health(1844) social(1437) communiti(874) }
{ structur(1116) can(940) graph(676) }
{ high(1669) rate(1365) level(1280) }
{ cancer(2502) breast(956) screen(824) }
{ use(976) code(926) identifi(902) }
{ drug(1928) target(777) effect(648) }
{ result(1111) use(1088) new(759) }
{ estim(2440) model(1874) function(577) }
{ method(1969) cluster(1462) data(1082) }
{ method(2212) result(1239) propos(1039) }
{ detect(2391) sensit(1101) algorithm(908) }

Resumo

The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

Resumo Limpo

hepat c virus hcv rna polymeras nsb lead target novel select hcv drug design enzym subject intens drug discoveri aim develop direct act antivir daa agent inhibit activ henc prevent virus replic genom studi focus one class nsb inhibitor name nucleostid mimet fortyon distinct nucleotid structur model within activ site nsb six major hcv genotyp comprehens model protocol employ differ molecular dynam simul combin molecular mechanicspoissonboltzmann surfac area mmpbsa methodolog rank analyz structur genotyp bind interact individu compound investig reduc atom level present studi signific refin understand mode action nsbnucleotideinhibitor identifi key structur element necessari activ implement tool rank potenti addit much need novel inhibitor nsb

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