J Chem Inf Model - Structural determinants of drug partitioning in n-hexadecane/water system.

Tópicos

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Resumo

Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of the transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristic because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 PC16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment-based prediction system, the PC16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the PC16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the fC16/W values were correlated with their more widely available counterparts for the 1-octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted PC16/W and PO/W values alone or the PC16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics.

Resumo Limpo

surrog phase wide use correl model transport partit drug biolog system take advantag chemic similar surrog phospholipid bilay elementari unit biolog phase respons transport partit solvat strata phospholipid bilay import drug characterist affect rate absorpt distribut well interact membran protein bind site locat insid bilay bilay core can emul nhexadecan c headgroup stratum often consid hydrophil phase high water content therefor test hypothesi cwater partit coeffici p can predict bilay locat drug small molecul better surrog system altogeth pcw valu nonioniz complet ioniz compound collect literatur measur necessari intent creat fragmentbas predict system pcw valu factor fragment solvat paramet f correct factor base clogp fragment scheme script pcw predict use clogp output provid expand predict system reveal solvat differ fcw valu correl wide avail counterpart octanolwat system ow use solvatochrom paramet analysi compound known bilay locat show avail predict pcw pow valu alon pco valu repres ratio satisfactorili predict prefer drug accumul bilay strata observ indic headgroup stratum albeit well hydrat solvat characterist similar water also poor describ ow partit characterist

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