title: Blocking the chaperone kinome pathway: mechanistic insights into a novel dual inhibition approach for supra-additive suppression of malignant tumors.
abstract: The chaperone Hsp90 is involved in regulating the stability and activation state of more than 200 'client' proteins and takes part in the cancer diseased states. The major clientele-protein kinases depend on Hsp90 for their proper folding and functioning. Cdc37, a kinase targeting co-chaperone of Hsp90, mediates the interactions between Hsp90 and protein kinases. Targeting of Cdc37 has the prospect of delivering predominantly kinase-selective molecular responses as compared to the current pharmacologic Hsp90 inhibitors. The present work reports a bio-computational study carried out with the aim of exploring the dual inhibition of Hsp90/Cdc37 chaperone/co-chaperone association complex by the naturally occurring drug candidates withaferin A and 17-DMAG along with their possible modes of action. Our molecular docking studies reveal that withaferin A in combination with 17-DMAG can act as potent chaperone system inhibitors. The structural and thermodynamic stability of the ligands' bound complex was also observed from molecular dynamics simulations in water. Our results suggest a novel tumor suppressive action mechanism of herbal ligands which can be looked forward for further clinical investigations for possible anticancer drug formulations.
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Agrawal
authors.forename: Piyush
authors.initials: P
authors.lastname: Pratik
authors.forename: Divya
authors.initials: D
authors.lastname: Bhasme
authors.forename: Virendra S
authors.initials: VS
authors.lastname: Bisaria
authors.forename: Durai
authors.initials: D
authors.lastname: Sundar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018833:Chaperonins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D018832:Molecular Chaperones; D054358:Withanolides; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D018833:Chaperonins; C009684:withaferin A