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Structure based approach to identify potent tissue selective andr | 44431
Journal of Proteomics & Bioinformatics

Journal of Proteomics & Bioinformatics
Open Access

ISSN: 0974-276X

+44 1223 790975

Structure based approach to identify potent tissue selective androgen receptor modulators


14th International Conference on Structural Biology

September 24-26, 2018 | Berlin, Germany

Ray Unwalla

Pfizer Inc, USA

Scientific Tracks Abstracts: J Proteomics Bioinform

Abstract :

The steroids testosterone and dihydrotestosterone (DHT) are androgens that play an important role in the development and maintenance of a variety of physiological responses such as male sexual function, bone density, muscle mass and strength. The androgen receptor is a nuclear hormone receptor that is expressed in many tissues and is responsible for mediating the actions of testosterone and DHT. Patients that have defects in the androgen receptor or have androgen deficiencies can be effectively treated with exogenous testosterone and other steroidal androgens as a hormone replacement therapy. The anabolic effects of testosterone have shown benefit in age related decline of bone density and muscle mass. However, the side effect profile of testosterone and other currently available anabolic steroids precludes their wide spread use and the chronic administration of steroidal androgens is associated with potential serious side effects such as hepatotoxicity, prostate hypertrophy and cancer. In addition, the oral bioavailability of testosterone is poor and the route of its administration is generally through topical formulations. We will describe our efforts to find novel series of oral tissue selective androgen receptor modulators (SARM) i.e., cyanopyrroles and indolines that selectively promote muscle growth while showing reduced androgenic effects on the prostate and seminal vesicles. Using a docking approach, we were able to delineate the binding mode of these series and further optimize the potency. An x-ray structure of a lead compound 7 bound to AR ligand binding domain revealed an interesting electrostatically unfavorable interaction of the 3-fluorophenol group with a carbonyl backbone of Leu704 residue. QM based intermolecular potential calculation performed to understand the strength of this interaction along with ligand strain energy calculations indicate a small energy penalty of ~0.6 kcal/mol paid by the ligand to adopt the bound state conformation. Recent Publications 1. Unwalla R et al., (2017) A structure-based approach to identify 5-[4-hydroxyphenyl]-pyrrole-2-carbonitrile derivatives as potent and tissue selective androgen receptor modulators. Journal of Medicinal Chemistry 60(14):6451-6457. 2. Saeed A et al., (2016) 2-Chloro-4[[(1R, 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A transdermal selective androgen receptor modulator (SARM) for muscle atrophy. Journal of Medicinal Chemistry 59(2):750-755. 3. Pollock J et al., (2015) Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes. Journal of Medicinal Chemistry 58(18):7465-7474. 4. Chekler E et al., (2014) 1-(2-hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulators. Journal of Medicinal Chemistry 57(6):2462-2471. 5. Bagatell C J (1996) Androgens in men �?? uses and abuses. New England Journal of Medicine 334(11):707-714.

Biography :

   

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