ABSTRACT
Chemical fragment spaces exceed traditional virtual compound libraries by orders of magnitude, making them ideal search spaces for drug design projects. However, due to their immense size, they are not compatible with traditional analysis and search algorithms that rely on the enumeration of molecules. In this paper, we present SpaceProp2, an evolution of the SpaceProp algorithm, which enables the calculation of exact property distributions for chemical fragment spaces without enumerating them. We extend the original algorithm by the capabilities to compute distributions for the TPSA, the number of rotatable bonds, and the occurrence of user-defined molecular structures in the form of SMARTS patterns. Furthermore, SpaceProp2 produces example molecules for every property bin, enabling a detailed interpretation of the distributions. We demonstrate SpaceProp2 on six established make-on-demand chemical fragment spaces as well as BICLAIM, the in-house fragment space of Boehringer Ingelheim. The possibility to search multiple SMARTS patterns simultaneously as well as the produced example molecules offers previously impossible insights into the composition of these vast combinatorial molecule collections, making it an ideal tool for the analysis and design of chemical fragment spaces.
Subject(s)
Algorithms , Drug Design , Molecular StructureABSTRACT
Vasopressin-activated calcium-mobilizing (VACM-1) protein is a cul-5 gene product that forms complexes with a subclass of ubiquitin E3 ligases involved in proteasomal protein degradation. The expression of VACM-1 cDNA in the T47D breast cancer cell line inhibits growth and decreases phosphorylation of mitogen activated protein kinase. Factors that regulate expression or stability of VACM-1 protein have not been identified, however. In our search to identify drugs/substances that may control VACM-1 protein expression, we examined the effects of resveratrol (trans-3,5,4'-trihydroxystilbene), a natural component in the human diet which inhibits tumor initiation and promotion. CMV vector and VACM-1 cDNA stably transfected T47D breast cancer-derived cells were treated with resveratrol and cell growth and VACM-1 protein concentrations were measured. Since the cellular mechanism of resveratrol-dependent inhibition of cell growth also involves the regulation of estrogen receptors, the effect of 17-ß-estradiol and resveratrol on ERα levels and on cell growth was examined in control and in VACM-1 cDNA transfected cells. Our results demonstrate that antiproliferative effect of resveratrol observed in the control T47D cancer cells was significantly enhanced in VACM-1 cDNA transfected T47D cells. Western blot results indicated that resveratrol increased VACM-1 protein concentration. Finally, treatment with resveratrol for 24 and 48 h attenuated 17-ß-estradiol induced increase in cell growth both in control and in VACM-1 cDNA transfected cells. The effect was significantly higher in the VACM-1 cDNA transfected cells when compared to controls. These results indicate that the antiproliferative effect of resveratrol may involve induction of VACM-1/cul5.
