Active target properties

CDK2 is involved with controlling normal cell proliferation. Disregulation in cancer makes this a good antitumor target. Pevarello et al. [62] describe the parallel optimization of enzyme inhibition potency, cellular activity, physicochemical properties, and PK. A low MW hit (MW = 201) was specifically selected with the... 

Careful prodrug design is required to minimize the number of proposed candidates and maximize the explored space of physicochemical and pharmacokinetic properties. The ability to predict target properties (e.g., solubility, extent of absorption, and rate of activation) is a major need in rational prodrug design, but global quantitative models simply do not exist, despite... 

Lastly, every research project presents a unique combination of parameters (target, assay methodology, hit rate, throughput limit, and so forth) and project team requirements for interesting actives (physiochemical properties, novelty, and so forth). This suggests that an optimal selection scheme should be easily tailored to meet these unique needs, which is certainly not true of a simple Top X approach. 

Typically, the final part of QSAR model development is the model validation [17, 18], when the predictive power of the model is tested on an independent set of compounds. In essence, predictive power is one of the most important characteristics of QSAR models. It can be defined as the ability of a model to predict accurately the target property (e.g., biological activity) of compounds that were not used for model development. The typical problem of QSAR modeling is that at the time of the model development a researcher only has, essentially, training set molecules, so predictive ability can only be characterized by statistical characteristics of the training set model and not by true external validation. 

Ramelteon is a hypnotic with melatonin receptor agonist activity targeting melatonin MTj and MT2 receptors. It has not been proven to induce dependence. As with zolpidem and zaleplon, no known anxiolytic properties have been elicited. No appreciable activity on serotonin, dopamine, GABA, or acetylcholine is present with the parent compound, but in vitro studies report that its primary metabolite M-II has weak 5-HT2g receptor agonist activity. 

More recently, the synthesis of an amine-phenol complex of gallium(III) was described (Fig. 10). The antimalarial activities were in the micromolar range against the HB3 CQ-susceptible and Dd2 CQ-resistant strains. The authors proposed that the cytotoxic targeting properties of these kinds of metal complexes lie in the spatial orientation of substituents on the peripheral part of the molecule [98]. 

Despite formal differences between various methodologies, any QSAR method is based on a QSAR table, which can be generalized, as shown in Fig. 2.2. To initiate a QSAR study, this table must include some identifiers of chemical structures (e.g., company s ID numbers, first column of the table in Fig. 2.2), reliably measured values of biological activity [or any other target property of interest (e.g., solubility, metabolic transformation rate, etc. ... 

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