Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Abstract

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.

A Computer-Assisted Systematic Search for Melatonin Derivatives with High Potential as Antioxidants

“…Four exclusion scores were used for that purpose. The first one, here referred to as S E,ADME2 is identical to that previously proposed (184,185) score, however, only accounts for 2 of the analyzed properties and has rather similar values for all the analyzed molecules (Fig. 2).…”

“…However, the selection score is rather general and might mask a particular case with high S S but a failure for a particular property. Therefore, in addition to S S , exclusion scores (S E ) were also used, inspired by previous proposals (184,185), to double-check if any molecule in the selected subset significantly deviates (in any of its properties) from the average value of the reference set (described in section 2.6). Four exclusion scores were used for that purpose.…”

Xanthenedione Derivatives, New Promising Antioxidant and Acetylcholinesterase Inhibitor Agents

“…Molecular properties such as the molecular weight, hydrophobicity (LogP), and the total polar surface area (TPSA) have been used extensively in modern drug discovery because they affect drug absorption, bioavailability, metabolism, toxicity as well as the hydrophobic drug-receptor interactions [20]. These and other parameters related with drug-likeness properties of xanthenediones 5 are listed in Table 3 [21].…”

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy

“…Highly lipophilc drugs (logP . 6) include the CAR ligand atorvastatin (Re zen et al, 2017), as well as montelukast, raloxifene, cinacalcet, fexofenadine, repaglinide, telmisartan, adapalene, terbinafine, dutasteride, and levothyroxine (Zhong et al, 2013). Many common environmental pollutants are lipophilic (logP .…”