CASSMedChem Research Group, DSTF at the Centre for Innovation, Università di Torino, Via Quarello 11, 10135, Torino, Italy.
Pharm Res. 2011 Mar;28(3):640-6. doi: 10.1007/s11095-010-0317-1. Epub 2010 Nov 17.
To describe a computational tool to calculate molecular descriptors of potential application in ADME virtual screening of antitumor Pt(II) drug candidates.
The multistep computational procedure consists in (a) building and optimization (PM3) of the 3D structures of the investigated complexes, (b) parametrization of Pt(II) and its implementation in GRID, (c) GRID calculations and extraction of the information content with VolSurf and BIOCUBE4mf, and (d) PLS analysis to look for the correlation between experimental data and the molecular descriptors.
The following results were obtained: (a) the calibration of the GRID force field to take into account the platinum di-cation, (b) solid PLS models between log k30 and log kw with VolSurf descriptors which highlight the main structural differences between the two chromatographic parameters, (c) the prediction of virtual (of each conformer) log k30 and log kw, and (d) the identification of the main descriptors governing VD(ss) of drugs in clinical use.
The study suggests a strategy to identify good Pt(II) complexes prior to their synthesis to eliminate as soon as possible drug candidates with unfavorable PK profile.
描述一种计算工具，用于计算在 ADME 虚拟筛选抗肿瘤 Pt(II)药物候选物中的潜在应用的分子描述符。
该多步计算程序包括(a) 研究复合物的 3D 结构的构建和优化（PM3），(b) Pt(II)的参数化及其在 GRID 中的实现，(c) GRID 计算和 VolSurf 和 BIOCUBE4mf 中的信息内容提取，以及(d) PLS 分析以寻找实验数据和分子描述符之间的相关性。
得到了以下结果：(a) 对 GRID 力场进行校准以考虑铂二价阳离子，(b) 在 VolSurf 描述符之间具有固体 PLS 模型，这些描述符突出了两个色谱参数之间的主要结构差异，(c) 虚拟（每个构象）log k30 和 log kw 的预测，以及(d) 识别临床使用药物 VD(ss)的主要描述符。
该研究提出了一种在合成之前识别良好的 Pt(II) 配合物的策略，以尽快消除具有不利 PK 特征的药物候选物。
