Combinatorial Chemistry & High Throughput Screening - Volume 14, Issue 5, 2011

The importance of optimizing Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) properties for potential drug candidates has been widely recognized. Although great progress has been made on high throughput (HT) ADME experimental assays, compared with high throughput screening (HTS) activity assays or combinatorial synthesis, the traditional ADME/T experiments still have low throughput cap Read More

The biopharmaceutical profile of a compound depends directly on the dissociation constants of its acidic and basic groups, commonly expressed as the negative decadic logarithm pKa of the acid dissociation constant (Ka). We survey the literature on computational methods to predict the pKa of small molecules. In this, we address data availability (used data sets, data quality, proprietary versus public data), molecular representat Read More

Aqueous solubility is one of the major physiochemical properties to be optimized in drug discovery. It is related to absorption and distribution in the ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity). Aqueous solubility and membrane permeability are the two key factors that affect a drug's oral bioavailability. Because of the importance of aqueous solubility, a lot of efforts have been spent on developing r Read More

The accurate prediction of the in vivo pharmacokinetics of a new potential drug compound based on only its virtual structure is the ultimate goal of in silico ADME-Tox property modeling. A comprehensive review is made on recent studies concerning the A (absorption) in ADME-Tox, i.e. the in silico modeling of both Caco-2 permeability and human intestinal absorption. The data sets used, the descriptors selected to build the m Read More

Unfavorable oral bioavailability is an important reason accounting for the failure of the drug candidates. Considering the lack of in vitro high-throughput screening assay for oral bioavailability, it is critical to develop in silico models for early predictions of oral bioavailability. In this review, we summarize present knowledge and recent progress related to the in silico prediction of oral bioavailability, including the current avail Read More

The risk for cardiotoxic side effects represents a major problem in clinical studies of drug candidates and regulatory agencies have explicitly recommended that all new drug candidates should be tested for blockage of the human Ether-a-go-go Related-Gene (hERG) potassium channel. Indeed, several drugs with different therapeutic indications and recognized as hERG blockers were recently withdrawn due to the risk of Read More

The application of combinatorial chemistry and high-throughput screening technique enables the large number of chemicals to be generated and tested simultaneously, which will facilitate the drug development and discovery. At the same time, it brings about a challenge of how to efficiently identify the potential drug candidates from thousands of compounds. A way used to deal with the challenge is to consider the drug phar Read More

Cytochrome P450 enzymes are the predominant mediators of phase I metabolism of exogenous small molecules. As a result of their extensive role in metabolism of xenobiotics, drug compounds, and endogenous compounds, as well as their wide tissue distribution, significant drug discovery resources are spent to avoid interacting with this class of enzymes. Here we review historical and recent in silico modeling of 7 cytochro Read More

Computational tools for predicting toxicity have been envisioned to have the potential to broadly impact up on the attrition rate of compounds in pre-clinical drug discovery and development. An integrated approach of computerassisted, predictive, and physico-chemical properties of a compound, along with its in vitro and in vivo analysis, needs to be routinely exercised in the lead identification and lead optimization pro Read More

Tingjun Hou is currently the Professor for the Institute of Functional Nano & Soft Materials (FUNSOM) at Soochow University in Suzhou, T.J. Hou's areas of scientific interest include: developing methods for computer-aided drug design (CADD) and designing potential lead compounds for important drug targets using the CADD techniques; inferring the proteinprotein interaction networks mediated by modular domains usin Read More