The proposed project focuses on two important enzymes involved in the hepatic metabolism/degradation of steroid hormones in the human body: 5α-reductase (SRD5A1) and 5β-reductase (AKR1D1). More exactly, both enzymes are very important in maintaining the androgen-glucocorticoid balance. Thus, any undesired interaction (inhibition) by small molecules (e.g. drugs, cosmetics, food additives, natural compounds) would result in altered activity of the enzymes and potentially lead to disruption of the steroid homeostasis. Increased levels of glucocorticoids may severely affect human health in terms of increased risk for development of metabolic diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatosis (NASH) [1-3].

The main goal of this project proposal is to develop in silico predictive models for screening of small molecules in order to rapidly and reliably identify their undesired interaction with the two enzymes. The project requests one year funding for a PhD student who will get training and subsequently apply various state-of-the-art modeling techniques like molecular docking, pose scoring, homology modeling, molecular dynamics simulations to elucidate enzyme-ligand interactions at the atomic level in silico as well as establish experimental activity assays for initial testing and validation of screening hits. The modelling information together with the enzyme activity data will allow defining structure-activity-relationships for the two enzymes.

1. Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW: 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. Endocrinology. 2015, 156(8):2863-71. doi: 10.1210/en.2015-1149.

2. Dowman JK, Hopkins LJ, Reynolds GM, Armstrong MJ, Nasiri M, Nikolaou N, van Houten EL, Visser JA, Morgan SA, Lavery GG, Oprescu A, Hübscher SG, Newsome PN, Tomlinson JW.: Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology. 2013, 154(12):4536-47. doi: 10.1210/en.2013-1592.

3. Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, Marshall I, Stewart LH, Walker BR, Andrew R.: 5α-reductase type 1 modulates insulin sensitivity in men. J. Clin. Endocrinol. Metab. 2014, 99(8):E1397-406. doi: 10.1210/jc.2014-1395.