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The genetic basis of character association related to differentiation found in the primary gene pool of rice was investigated based on the genomic distribution of quantitative trait loci (QTLs). Major evolutionary trends in cultivated rice of Asiatic origin ( Oryza sativa) and its wild progenitor ( O. rufipogon) are: (1) differentiation from wild to domesticated types (domestication), (2) ecotype differentiation between the perennial and annual types in wild races, and (3) the Indica versus Japonica type differentiation in cultivated races. Using 125 recombinant inbred lines (RILs) derived from a cross between an Indica cultivar of O. sativa and a strain of O. rufipogon carrying some Japonica-like characteristics, we mapped 147 markers, mostly RFLPs, on 12 chromosomes. Thirty-seven morphological and physiological quantitative traits were evaluated, and QTLs for 24 traits were detected. The mapped loci showed a tendency to form clusters that are composed of QTLs of the domestication-related traits as well as Indica/Japonica diagnostic traits. QTLs for perennial/annual type differences did not cluster. This cluster phenomenon could be considered "multifactorial linkages" followed by natural selection favoring co-adapted traits. Further, it is possible that the clustering phenomenon is partly due to pleiotropy of some unknown key factor(s) controlling various traits through diverse metabolic pathways. Chromosomal regions where QTL clusters were found coincided with the regions harboring genes or gene blocks where the frequency of cultivar-derived alleles in RILs is higher than expected. This distortion may be partly due to unconscious selection favoring cultivated plant type during the establishment of RILs.

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As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC(50) = 0.10 microM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC(50) = 0.042 microM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.

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