Phosphodiesterase-4 (PDE-4) is an important drug target for several diseases, including COPD (chronic obstructive pulmonary disorder) and neurodegenerative diseases. In this paper, we describe the development of improved QSAR (quantitative structure-activity relationship) models using a novel multi-conformational structure-based pharmacophore key (MC-SBPPK) method. Similar to our previous work, this method calculates molecular descriptors based on the matching of a molecule's pharmacophore features with those of the target binding pocket. Therefore, these descriptors are PDE4-specific, and most relevant to the problem under study. Furthermore, this work expands our previous SBPPK QSAR method by explicitly including multiple conformations of the PDE-4 inhibitors in the regression analysis, and thus addresses the issue of molecular flexibility. The nonlinear regression problem resulted from including multiple conformations has been transformed into a linear equation and solved by an iterative partial least square (iPLS) procedure, according to the Lukacova-Balaz scheme. 35 PDE-4 inhibitors have been analyzed with this new method, and predictive models have been developed. Based on the prediction statistics for both the training set and the test set, these new models are more robust and predictive than those obtained by traditional ligand-based QSAR techniques as well as that obtained with the SBPPK method reported in our previous work. As a result, multiple predictive models have been added to the collection of QSAR models for PDE4 inhibitors. Collectively, these models will be useful for the discovery of new drug candidates targeting the PDE-4 enzyme.

The modern industrial application of lemon is significantly associated with their juicy materials obtained from the pulpy region, leaving behind a remarkable mass of by-products which are often discarded as waste. Several studies have shown that materials obtained from all handling and processing operations have substantial biological benefits based on their concomitant phytochemistry. In addition, these materials have been found suitable as raw substrates for the syntheses and manufacturing of various food-based additives. This research succinctly delineates these concepts and offers a comprehensive framework of its etymology, rich history, and overall pomology. More importantly, recently studied underlying biochemical mechanisms for the actions of lemon and its by-products for metabolic disorders such as diabetes, cancer and hypertension are technically delineated. These materials have been appraised as natural sources for nutraceuticals studied to be potential alternatives to typical synthetic pharmaceutics.

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