Department of Chemistry, University of Nebraska at Omaha, DSC 362, 6001 Dodge Street, Omaha, NE 68182, USA.
Curr Top Med Chem. 2013;13(11):1290-307. doi: 10.2174/15680266113139990034.
Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski's rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas.
分子性质，如分子量、疏水性参数 logP 和总极性表面积（TPSA），已广泛应用于现代药物发现。我们研究了这些性质和美国零售销售额（2010 年）排名前 200 种治疗药物的 ADMET 评分，并根据临床适应症和/或给药途径对其进行了分类。这些药物列表为成功批准的药物提供了这些分子描述符的大量信息。口服药物的平均 logP 为 2.5，而注射用药物的 logP 似乎较小。在不同类型的临床适应症中，用于抗 HIV 和抗生素的药物往往具有较低的 logP。抗 HIV 药物、抗高血压药和抗生素的分子量似乎较大。ADMET 评分是通过分子量和 logP 的组合得出的，对于口服药物来说是一致的，平均得分为 1.5，标准差为 1.0。许多违反 Lipinski 五规则的临床药物仍然可以表现出非常接近口服药物（1.5）的 ADMET 评分，并在可接受的标准差范围内。分子量、logP 和 TPSA 的分子性质似乎根据其临床适应症而有所不同。许多药物与酸或溶剂形成盐或共晶，从而提高其溶解度。我们的数据表明，添加盐酸盐是提高药物成分溶解度最常见的方法。细胞色素 P450 同工酶 3A4、2D6、2C9、2C8 和 3C5 是代谢 200 种最常用药物的前五种蛋白质。由 3A4 代谢的药物似乎分子量较大，而由 2D6 代谢的药物分子量较小。由 CYP2C8 代谢的药物似乎最亲水，logP 最小，极性表面积最大。
