J Chem Inf Model - Accuracy assessment and automation of free energy calculations for drug design.

Tópicos

{ bind(1733) structur(1185) ligand(1036) }
{ error(1145) method(1030) estim(1020) }
{ measur(2081) correl(1212) valu(896) }
{ studi(1410) differ(1259) use(1210) }
{ sampl(1606) size(1419) use(1276) }
{ surgeri(1148) surgic(1085) robot(1054) }
{ network(2748) neural(1063) input(814) }
{ treatment(1704) effect(941) patient(846) }
{ use(1733) differ(960) four(931) }
{ drug(1928) target(777) effect(648) }
{ can(774) often(719) complex(702) }
{ system(1976) rule(880) can(841) }
{ concept(1167) ontolog(924) domain(897) }
{ clinic(1479) use(1117) guidelin(835) }
{ extract(1171) text(1153) clinic(932) }
{ design(1359) user(1324) use(1319) }
{ research(1085) discuss(1038) issu(1018) }
{ data(2317) use(1299) case(1017) }
{ group(2977) signific(1463) compar(1072) }
{ model(3404) distribut(989) bayesian(671) }
{ assess(1506) score(1403) qualiti(1306) }
{ framework(1458) process(801) describ(734) }
{ problem(2511) optim(1539) algorithm(950) }
{ data(1714) softwar(1251) tool(1186) }
{ compound(1573) activ(1297) structur(1058) }
{ studi(1119) effect(1106) posit(819) }
{ monitor(1329) mobil(1314) devic(1160) }
{ model(2656) set(1616) predict(1553) }
{ data(3008) multipl(1320) sourc(1022) }
{ structur(1116) can(940) graph(676) }
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{ record(1888) medic(1808) patient(1693) }
{ health(3367) inform(1360) care(1135) }
{ model(3480) simul(1196) paramet(876) }
{ ehr(2073) health(1662) electron(1139) }
{ state(1844) use(1261) util(961) }
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{ patient(2837) hospit(1953) medic(668) }
{ age(1611) year(1155) adult(843) }
{ medic(1828) order(1363) alert(1069) }
{ signal(2180) analysi(812) frequenc(800) }
{ cost(1906) reduc(1198) effect(832) }
{ gene(2352) biolog(1181) express(1162) }
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{ health(1844) social(1437) communiti(874) }
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{ implement(1333) system(1263) develop(1122) }
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{ activ(1452) weight(1219) physic(1104) }
{ method(1969) cluster(1462) data(1082) }
{ detect(2391) sensit(1101) algorithm(908) }

Resumo

As the free energy of binding of a ligand to its target is one of the crucial optimization parameters in drug design, its accurate prediction is highly desirable. In the present study we have assessed the average accuracy of free energy calculations for a total of 92 ligands binding to five different targets. To make this study and future larger scale applications possible we automated the setup procedure. Starting from user defined binding modes, the procedure decides which ligands to connect via a perturbation based on maximum common substructure criteria and produces all necessary parameter files for free energy calculations in AMBER 11. For the systems investigated, errors due to insufficient sampling were found to be substantial in some cases whereas differences in estimators (thermodynamic integration (TI) versus multistate Bennett acceptance ratio (MBAR)) were found to be negligible. Analytical uncertainty estimates calculated from a single free energy calculation were found to be much smaller than the sample standard deviation obtained from two independent free energy calculations. Agreement with experiment was found to be system dependent ranging from excellent to mediocre (RMSE = [0.9, 8.2, 4.7, 5.7, 8.7] kJ/mol). When restricting analyses to free energy calculations with sample standard deviations below 1 kJ/mol agreement with experiment improved (RMSE = [0.8, 6.9, 1.8, 3.9, 5.6] kJ/mol).

Resumo Limpo

free energi bind ligand target one crucial optim paramet drug design accur predict high desir present studi assess averag accuraci free energi calcul total ligand bind five differ target make studi futur larger scale applic possibl autom setup procedur start user defin bind mode procedur decid ligand connect via perturb base maximum common substructur criteria produc necessari paramet file free energi calcul amber system investig error due insuffici sampl found substanti case wherea differ estim thermodynam integr ti versus multist bennett accept ratio mbar found neglig analyt uncertainti estim calcul singl free energi calcul found much smaller sampl standard deviat obtain two independ free energi calcul agreement experi found system depend rang excel mediocr rmse kjmol restrict analys free energi calcul sampl standard deviat kjmol agreement experi improv rmse kjmol

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