Current knowledge of the multifunctional 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1).

At the late 1940s, 17ß-HSD1 was discovered as the first member of the 17ß-HSD family with its gene cloned. The three-dimensional structure of human 17ß-HSD1 is the first example of any human steroid converting enzyme. The human enzyme's structure and biological function have thus been studied extensively in the last two decades. In humans, the enzyme is expressed in placenta, ovary, endometrium and breast. The high activity of estrogen activation provides the basis of 17ß-HSD1's implication in estrogen-dependent diseases, such as breast cancer, endometriosis and non-small cell lung carcinomas. Its dual function in estrogen activation and androgen inactivation has been revealed in molecular and breast cancer cell levels, significantly stimulating the proliferation of such cells. The enzyme's overexpression in breast cancer was demonstrated by clinical samples. Inhibition of human 17ß-HSD1 led to xenograft tumor shrinkage. Unfortunately, through decades of studies, there is still no drug using the enzyme's inhibitors available. This is due to the difficulty to get rid of the estrogenic activity of its inhibitors, which are mostly estrogen analogues. New non-steroid inhibitors for the enzyme provide new hope for non-estrogenic inhibitors of the enzyme.

Identification of novel potent inhibitors against Bcl-xL anti-apoptotic protein using docking studies.

Bcl-xL protein belongs to BCL-2 family which has either pro- or anti-apoptotic activities owing to their importance in the regulation of apoptosis, tumor genesis and cellular responses to anti-cancer therapy. Bcl-xL permeabilize the outer mitochondrial membrane of cells and inhibit these processes. Protein-inhibitor interactions play an important role in regulating the expression of Bcl-xL protein. Here, we report the docking studies that resulted in the identification of new inhibitors distinct from the previously reported inhibitor against this protein. The results have been validated using Sybyl surflux docking. New potent inhibitors from docking analysis are pentacyclic triterpenoid derivative (2S,4aR,6aR, 6bS,8aS,10R,12R,12aS,12bR,14bR,E)-10,12-dihydroxy-2,4a,14b-trimethyl-9-((((R)-3,4,5-trihydroxy-6-methyl-2H-pyran- 2-yl)oxy)methylene)-1,2,3,4,4a,5,6,6a,6b,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-car-boxylic acid and 4- alkyl-4-methoxypiperidine derivative 8h (where R= 4-Cl-Ph) that promotes the release of pro-apoptotic proteins from the mitochondria which is a key event in cell death signaling. The compounds form stable complex with protein exhibiting highest binding affinity and Gibbs free energy. Pentacyclic triterpenoid derivatives compound-201 and piperidine derivative compound-39 are potent inhibitors with Ki value of 172.62nM and 175.24 nM high affinity and inhibitory potency. Salt bridge, pi-pi and hydrogen bonding interactions predominantly contribute towards the stability of the complexes. These compounds can further be exploited for their potential to enhance apoptosis. We have established the correlation between the experimental Ki value with our computational inhibition constant. The quantitative predictions in this study provide a scope for further experimental testing giving structural insights into the design and development of novel anticancer drugs.