Fragment based discovery of arginine isosteres through REPLACE: Towards non-ATP competitive CDK inhibitors |
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| Institution: | 1. Molecular Model Discovery Laboratory, Department of Chemistry and Biotechnology, School of Science, Faculty of Science, Engineering and Technology, Swinburne University of Technology, PO Box 218, Hawthorn, Victoria, 3122, Australia;2. School of Physics and Optoelectronic Engineering, Ludong University, Shandong, Yantai, 264025, PR China;1. Homi Bhabha National Institute, Mumbai 400094, India;2. Atomic and Molecular Physics Division, BARC, Trombay, Mumbai 400085, India;3. Indus Operation and Accelerator Physics Development Division, RRCAT, Indore, India;1. Department of Physiology, School of Medicine, Universidad Nacional Autónoma de México (UNAM), Apartado Postal 70250, C.P. 04510 México, D.F., México;2. Section of Bioelectronics, Department of Electrical Engineering, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14740, C.P. 07000 México, D.F., México;3. Department of Psychological and Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, IN 47405, USA;1. CEMDRX, Department of Physics, University of Coimbra, Rua Larga, P-3004-516 Coimbra, Portugal;2. Advanced Materials Laboratory, ETSIIAA, Universidad de Valladolid, Avenida de Madrid 44, 34004 Palencia, Spain;3. MALTA Consolider Team, and Department of Fundamental and Experimental Physics, Electronics and Systems, Universidad de La Laguna, E-38200 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain;4. Higher Technical School of Telecommunications Engineering, Universidad de Valladolid, Campus Miguel Delibes, Paseo Belén 15, 47011 Valladolid, Spain |
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| Abstract: | In order to develop non-ATP competitive CDK2/cyclin A inhibitors, the REPLACE strategy has been applied to generate fragment alternatives for the N-terminal tetrapeptide of the cyclin binding motif (HAKRRLIF) involved in substrate recruitment prior to phosphotransfer. The docking approach used for the prediction of small molecule mimics for peptide determinants was validated through reproduction of experimental binding modes of known inhibitors and provides useful information for evaluating binding to protein–protein interaction sites. Further to this, potential arginine isosteres predicted using the validated LigandFit docking method were ligated to the truncated C-terminal peptide, RLIF using solid phase synthesis and evaluated in a competitive binding assay. After testing, identified fragments were shown to represent not only appropriate mimics for a critical arginine residue but also to interact effectively with a minor hydrophobic pocket present in the binding groove. Further evaluation of binding modes was undertaken to optimize the potency of these compounds. Through further application of the REPLACE strategy in this study, peptide-small molecule hybrid CDK2 inhibitors were identified that are more drug-like and suitable for further optimization as anti-tumor therapeutics. |
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| Keywords: | Cyclin dependent kinase Drug discovery Inhibitor Anti-tumor therapeutic REPLACE |
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