Gumede NJ, Prospective computational design and in vitro bio-analytical tests of new.pdf (1.34 MB)
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Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors

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posted on 2022-01-06, 08:48 authored by N.J. Gumede, W. Nxumalo, K. Bisetty, L. Escuder-Gilabert, M.J. Medina-Hernandez
The development and advancement of prostate cancer (PCa) into stage 4, where it metastasize, is a major problem mostly in elder males. The growth of PCa cells is stirred up by androgens and androgen receptor (AR). Therefore, therapeutic strategies such as blocking androgens synthesis and inhibiting AR binding have been explored in recent years. However, recently approved drugs (or in clinical phase) failed in improving the ex?pected survival rates for this metastatic-castration resistant prostate cancer (mCRPC) patients. The selective CYP17A1 inhibition of 17,20-lyase route has emerged as a novel strategy. Such inhibition blocks the production of androgens everywhere they are found in the body. In this work, a three dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore model is developed on a diverse set of non-steroidal inhibitors of CYP17A1 enzyme. Highly active compounds are selected to define a six-point pharmacophore hypothesis with a unique geometrical arrangement fitting the following description: two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two aromatic rings (R). The QSAR model showed adequate predictive statistics. The 3D-QSAR model is further used for database virtual screening of potential inhibitory hit structures. Density functional theory (DFT) optimization provides the electronic properties explaining the reactivity of the hits. Docking simulations discovers hydrogen bonding and hydrophobic interactions as responsible for the binding affinities of hits to the CYP17A1 Protein Data Bank structure. 13 hits from the database search (including five derivatives) are then synthesized in the laboratory as different scaffolds. Ultra high performance liquid chro?matography-tandem mass spectrometry (UHPLC-MS/MS) in vitro experiments reveals three new chemical en?tities (NCEs) with half maximal inhibitory concentration (IC50) values against the lyase route at mid-micromolar range with favorable selectivity to the lyase over the hydroxylase route (one of them with null hydroxylase inhibition). Thus, prospective computational design has enabled the design of potential lead lyase-selective inhibitors for further studies.


This work research work was supported financially in part by the National Research Foundation of South Africa and First Rand Foundation (UID: 112151). This work was also made possible through funding by the Research Capacity Development Initiative-South African Medical Research Council (RCDI-SAMRC). The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of NRF and SAMRC. The authors would like to acknowledge the Centre for High Performance Computing for allowing access to their resources for molecular modeling. Xenogesis Ltd is greatly acknowledge for performing bioanalytical experiments, as an outsourced services. Enamine LTD is greatly acknowledge for custom synthesis of the compounds, as an outsourced service.