In silico drug discovery is a complex process requiring flexibility and ingenuity in method selection and a careful validation of work protocols. GPCR in silico drug discovery poses additional challenges due to the paucity of crystallographic data. This paper starts by reviewing selected GPCR in silico screening programs reported in the literature, including both structure-based and ligand-based approaches. Particular emphasis is given to library design, binding mode selection, process validation and compound selection for biological testing. Following literature review, we provide insights into in silico methodologies and process workflows used at EPIX and previously at PREDIX to drive over 20 highly successful screening and lead optimization programs performed since 2001. Applications of the various methodologies discussed are demonstrated by examples from recent programs that have not yet been published.

ABSTRACT Multiplication of Euglena cells treated by 0-5-1-0 mg/ml chloramphenicol was not disturbed for the first 36 h and inhibition appeared only at later stages. The mean cell volume of treated dividing cells was decreased, although the initial rise in cell volume, which normally occurred during the first 12 h of incubation, was not prevented. The antibiotic also lowered the chlorophyll content of green dividing cells. In dark-grown cells transferred to light, inhibition of chlorophyll synthesis was immediate but not complete, and was followed by a decreased rate of plastid elongation and thylakoid formation. Our findings suggest that chloramphenicol does not cause the loss of existing pigment and that impaired chlorophyll synthesis is a secondary effect of inhibition of protein synthesis. The results also indicate that the greening process is more sensitive than cell division to the antibiotic.