Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
ChemMedChem. 2013 Feb;8(2):242-55. doi: 10.1002/cmdc.201200507. Epub 2013 Jan 9.
Chemogenomics methods seek to characterize the interaction between drugs and biological systems and are an important guide for the selection of screening compounds. The acid/base character of drugs has a profound influence on their affinity for the receptor, on their absorption, distribution, metabolism, excretion and toxicity (ADMET) profile and the way the drug can be formulated. In particular, the charge state of a molecule greatly influences its lipophilicity and biopharmaceutical characteristics. This study investigates the acid/base profile of human small-molecule drugs, chemogenomics datasets and screening compounds including a natural products set. We estimate the acid-ionization constant (pK(a)) values of these compounds and determine the identity of the ionizable functional groups in each set. We find substantial differences in acid/base profiles of the chemogenomic classes. In many cases, these differences can be linked to the nature of the target binding site and the corresponding functional groups needed for recognition of the ligand. Clear differences are also observed between the acid/base characteristics of drugs and screening compounds. For example, the proportion of drugs containing a carboxylic acid was 20 %, in stark contrast to a value of 2.4 % for the screening set sample. The proportion of aliphatic amines was 27 % for drugs and only 3.4 % for screening compounds. This suggests that there is a mismatch between commercially available screening compounds and the compounds that are likely to interact with a given chemogenomic target family. Our analysis provides a guide for the selection of screening compounds to better target specific chemogenomic families with regard to the overall balance of acids, bases and pK(a) distributions.
化学生物基因组学方法旨在研究药物与生物系统之间的相互作用，是筛选化合物选择的重要指导。药物的酸碱特性对其与受体的亲和力、吸收、分布、代谢、排泄和毒性（ADMET）特征以及药物的制剂方式有深远影响。特别是，分子的电荷状态极大地影响其亲脂性和生物制药特性。本研究调查了人类小分子药物、化学生物基因组学数据集和筛选化合物（包括天然产物集）的酸碱特性。我们估计了这些化合物的酸离解常数（pK(a)）值，并确定了每个集合中可离解官能团的身份。我们发现化学生物基因组学类别的酸碱特性存在显著差异。在许多情况下，这些差异可以与靶结合位点的性质以及识别配体所需的相应官能团联系起来。药物和筛选化合物之间的酸碱特性也存在明显差异。例如，含有羧酸的药物比例为 20%，而筛选集样本的比例仅为 2.4%。药物中的脂肪族胺比例为 27%，而筛选化合物的比例仅为 3.4%。这表明，商业上可用的筛选化合物与可能与特定化学生物基因组靶家族相互作用的化合物之间存在不匹配。我们的分析为筛选化合物的选择提供了指导，以便更好地针对特定的化学生物基因组家族，考虑到酸、碱和 pK(a)分布的整体平衡。
