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

Rampogu, Shailima; Parate, Shraddha; Saravanan, P.; Park, Chanin; Baek, Ayoung; Son, Maeng-Hyun; Park, Yohan; Park, Seok Ju; Lee, Keun Woo

doi:10.1016/j.compbiolchem.2019.107113

Cited by 30 publications

(31 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Encouraged from the above-mentioned efforts, we designed a pharmacophore-based virtual screening strategy [ 30 , 35 , 42 , 43 , 44 , 45 , 46 ] combined with molecular docking and molecular dynamics simulations to acquire flavonoids as effective WT and MT ROS-1 RTK inhibitors. Accordingly, a receptor-ligand pharmacophore model was developed deriving HBA, HBD and Hy as key pharmacophoric features ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

et al. 2021

Self Cite

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase is one of its clinically relevant oncogenic markers. The ROS-1 inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against the mutated kinase. In the present study, a receptor-ligand pharmacophore model exploiting the key features of lorlatinib binding with ROS-1 was exploited to identify inhibitors against the wild-type (WT) and the mutant (MT) kinase domain. The developed model was utilized to virtually screen the TimTec flavonoids database and the retrieved drug-like hits were subjected for docking with the WT and MT ROS-1 kinase. A total of 10 flavonoids displayed higher docking scores than lorlatinib. Subsequent molecular dynamics simulations of the acquired flavonoids with WT and MT ROS-1 revealed no steric clashes with the Arg2032 (MT ROS-1). The binding free energy calculations computed via molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) demonstrated one flavonoid (Hit) with better energy than lorlatinib in binding with WT and MT ROS-1. The Hit compound was observed to bind in the ROS-1 selectivity pocket comprised of residues from the β-3 sheet and DFG-motif. The identified Hit from this investigation could act as a potent WT and MT ROS-1 inhibitor.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mechanism is reminiscent to that of other anticancer molecules that block Hsp90, such as geldanamycin and compound Y306zh, which binds tightly to the NH2‐terminus of Hsp90 (N. Xue et al, 2014). There are many Hsp90 inhibitors endowed with anticancer properties (Dutta Gupta, Bommaka, & Banerjee, 2019; Rampogu et al, 2019). AIT would bind to the p23 partner of Hsp90, thereby also destabilizing certain Hsp90 client proteins, in a manner similar to the pentacyclic triterpenoid gedunin (Figure 4) which is known to bind to p23, thus blocking its cellular interaction with Hsp90, causing apoptotic cell death (Patwardhan et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Anticancer properties and mechanism of action of the quassinoid ailanthone

Bailly

2020

Phytotherapy Research

View full text Add to dashboard Cite

Ailanthone (AIT) is a quassinoid natural product isolated from the worldwide‐distributed plant Ailanthus altissima. The drug displays multiple pharmacological properties, in particular significant antitumor effects against a variety of cancer cell lines in vitro. Potent in vivo activities have been evidenced in mice bearing hepatocellular carcinoma, nonsmall cell lung cancer and castration‐resistant prostate cancer. This review focusses on the mechanism of action of AIT, notably to highlight the capacity of the drug to activate DNA damage responses, to inhibit the Hsp90 co‐chaperone p23 and to modulate the expression of several microRNA. The interconnexion between these effects is discussed. The unique capacity of AIT to downregulate oncogenic miR‐21 and to upregulate the tumor suppressor miRNAs miR‐126, miR‐148a, miR‐195, and miR‐449a is presented. AIT exploits several microRNAs to exert its anticancer effects in distinct tumor types. AIT is one of the rare antitumor natural products that binds to and strongly inhibits cochaperone p23, opening interesting perspectives to treat cancers. However, the toxicity profile of the molecule may limit its development as an anticancer drug, unless it can be properly formulated to prevent AIT‐induced gastro‐intestinal damages in particular. The antitumor properties of AIT and analogs are underlined, with the aim to encourage further pharmacological studies with this underexplored natural product and related quassinoids. Highlights Ailanthone (AIT) is an anticancer quassinoid isolated from Ailanthus altissima It inhibits proliferation and induces cell death of many cancer cell types The drug activates DNA damage response and targets p23 cochaperone Up or downregulation of several microRNA by AIT contributes to the anticancer activity Analogs or specific formulations must be developed to prevent the toxicity of AIT

show abstract

“…It was also the case for logP, the H-bond donor, and the acceptor. If the limit of Lipinski's rule of ve is violated by a candidate inhibitor, the candidates may not be suitable for laboratory synthesis 60 . Lipinski's rule of ve still shows that nel navir has good criteria to be a drug candidate for this viral virus.…”

Section: Discussionmentioning

confidence: 99%

Molecular Docking Studies of SARS-Cov-2 Mainprotease Potential Inhibitors

Utami¹,

Fitriani

Aziz

et al. 2020

Preprint

View full text Add to dashboard Cite

BACKGROUND : SARS-Cov-2 causes an coronavirus disease 2019 (COVID-19), and the vaccines or drugs of this disease have not been found to inhibit this replication of the virus. Researchers are engaged in all fields of study to discover new potential inhibitors. This study aimed to compute the binding energy (BE) and interactions between the new potential inhibitors and the SARS-Cov-2 Mainprotease (Mpro).METHODS: In this study, we docked between twenty-seven patented drugs and the Mpro receptor (PDB ID: 6W63). The molecular docking calculation was performed using AutoDock Tools 1.5.6. software. Moreover, the information about the biological activity of ligands was calculated using the PASS online server. The result of the calculation was then analyzed and visualized using Biovia Discovery Studio Visualizer. Further calculation, such as the ligand-protein interaction using STITCH database and Lipinski’s rule five were employed in this research.RESULTS: The molecular docking calculation results showed that nelfinavir was strongly bound to Mpro with BE of -9,51 kcal/mol, followed by lopinavir, vitamin D, ritonavir, and dexamethasone. From these ligands, we considered dexamethasone because this ligand works as an anti-inflammatory agent. CONCLUSIONS: Following the calculation, nelfinavir, lopinavir, and dexamethasone are proposed as a potential inhibitor of the Mpro receptor, but there is a need for further investigation.

show abstract

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

Cited by 30 publications

References 49 publications

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Anticancer properties and mechanism of action of the quassinoid ailanthone

Molecular Docking Studies of SARS-Cov-2 Mainprotease Potential Inhibitors

Contact Info

Product

Resources

About