Natural compounds as potential Hsp90 inhibitors for breast cancer-Pharmacophore guided molecular modelling studies.

Published on Dec 1, 2019in Computers in Biology and Medicine2.29
· DOI :10.1016/j.compbiolchem.2019.107113
Shailima Rampogu7
Estimated H-index: 7
(Gyeongsang National University),
Shraddha Parate1
Estimated H-index: 1
(Gyeongsang National University)
+ 6 AuthorsKeun Woo Lee30
Estimated H-index: 30
(Gyeongsang National University)
Abstract Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present in silico investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski’s rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds – Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.
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#1Shailima Rampogu (Gyeongsang National University)H-Index: 7
#2Minky Son (Gyeongsang National University)H-Index: 8
Last.Keun Woo Lee (Gyeongsang National University)H-Index: 30
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#1Maryam Abbasi (IUMS: Isfahan University of Medical Sciences)H-Index: 7
#2Hojjat Sadeghi-Aliabadi (IUMS: Isfahan University of Medical Sciences)H-Index: 15
Last.Massoud Amanlou (Tehran University of Medical Sciences)H-Index: 24
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#1Maria Giovanna Chini (UNISA: University of Salerno)H-Index: 17
#2Nicola Malafronte (UNISA: University of Salerno)H-Index: 10
Last.Fabrizio Dal Piaz (UNISA: University of Salerno)H-Index: 26
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#1Sharad Verma (JNU: Jawaharlal Nehru University)H-Index: 4
#2Sukriti Goyal (Banasthali Vidyapith)H-Index: 15
Last.Abhinav Grover (JNU: Jawaharlal Nehru University)H-Index: 18
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#1Tariq IsmailH-Index: 11
#2Cinzia CalcabriniH-Index: 11
Last.P. Sestilli (University of Urbino)H-Index: 30
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