Journal ArticleDOI
Discovery of small molecule inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulation and experimental validation against myeloid cell leukemia-1 (Mcl-1).
Muhammad R. Suleiman,Hanxun Wang,Danxia Huang,Huibin Wang,Johnson Joseph,Tianci Huang,Fengjiao Zhang,Jian Wang,Maosheng Cheng +8 more
TLDR
The present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.Abstract:
Myeloid cell leukemia-1 (Mcl-1) protein is a family of Bcl-2 (B cell lymphoma 2) rich proteases of the most common increase threshold for genetic aberrations observed in human cancer, including lung, breast, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma. Mcl-1 is recognized as an attractive drug target in number of diseases, including cancer. In the present study we surveyed and collected queries compounds from PDB database of Mcl-1 protein and generated pharmacophore-based models adapted to screen the drug-like compounds from FDA approved database. The 206 best lead molecules from pharmacophore-screening were further evaluated by molecular docking, molecular dynamics simulation, MM-GBSA calculation, as well as experimental validation. Two hits, ZINC00601272 and ZINC00002166, showed the best docking scores, which showed a tendency to inhibit cell viability of HL60 and K562 leukemia cells with Mcl-1 expressions. Conclusively, the present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.Communicated by Ramaswamy H. Sarma.read more
Citations
More filters
Journal ArticleDOI
Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein - an in silico insight into the comparative efficacy of repurposing antiviral drugs.
Muhammad Amin,Ghazanfer Abbas +1 more
TL;DR: The recommended doses of Hydroxychloroquine may reduce the chances of catching to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with SARS-CoV-2.
Journal ArticleDOI
Proteome profiling reveals the efficacy and targets of sophocarpine against asthma.
Zhi Wenbing,Xia Du,Ye Li,Chunliu Wang,Sun Tingting,Zong Shiyu,Qiqi Liu,Kai Hu,Yang Liu,Zhang Hong +9 more
TL;DR: Sophocarpine (SPC) as a quinolizidine alkaloid displays powerful effects on inflammatory diseases through regulating multiple targets as discussed by the authors, which is a complex heterogeneous and inflammatory disease with an increasing incidence worldwide.
Journal ArticleDOI
Identification of natural compounds targeting SARS-CoV-2 Mpro by virtual screening and molecular dynamics simulations
TL;DR: Using molecular docking and molecular dynamics simulations, a total of 5600 natural compounds available for virtual screening were tested to identify potential inhibitors of SARS-CoV-2 Mpro as mentioned in this paper .
Posted ContentDOI
Sulforaphane Enhances the Anticancer Properties of Paclitaxel in Two Human Derived Prostate Cancer Cell Lines
TL;DR: In this article , the effect of PTX or SFN on reducing cell viability increased in a dose-dependent manner, and the combined treatment enhanced these effects in favor of cell apoptosis versus survival.
Journal ArticleDOI
Discovery of Mcl-1 inhibitors through virtual screening, molecular dynamics simulations and in vitro experiments
Jianda Yue,Yaqi Li,Fengjiao Li,Peng Zhang,Yimin Li,Jiawei Xu,Qianqian Zhang,Cheng-jun Zhang,Xiao Lang He,Ying Wang,Zhong-Yi Liu +10 more
TL;DR: Wang et al. as discussed by the authors obtained a series of small molecules with a common core skeleton through molecular docking from Specs database and searched the core structure in ZINC database for more similar small molecules.
References
More filters
Journal ArticleDOI
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
András Kotschy,Szlávik Zoltán,James A. H. Murray,James Edward Paul Davidson,Ana Leticia Maragno,Gaëtane Le Toumelin-Braizat,Maïa Chanrion,Gemma L. Kelly,Gemma L. Kelly,Jia-Nan Gong,Jia-Nan Gong,Donia M Moujalled,Alain Bruno,Csékei Márton,Attila Paczal,Zoltán B. Szabó,Szabolcs Sipos,Gabor Radics,Proszenyák Ágnes,Balázs Bálint,Levente Ondi,Gábor Blasko,Alan P. Robertson,Allan E. Surgenor,Pawel Dokurno,Chen I-Jen,Natalia Matassova,Julia Smith,C. Pedder,Chris Graham,Aurélie Studeny,Gaëlle Lysiak-Auvity,Anne-Marie Girard,Fabienne Gravé,David J. Segal,David J. Segal,Chris D. Riffkin,Chris D. Riffkin,Giovanna Pomilio,Laura C. A. Galbraith,Laura C. A. Galbraith,Brandon J. Aubrey,Brandon J. Aubrey,Brandon J. Aubrey,Margs S. Brennan,Margs S. Brennan,Marco J Herold,Marco J Herold,Catherine Chang,Catherine Chang,Ghislaine Guasconi,Nicolas Cauquil,Fabien Melchiore,Nolwen Guigal-Stephan,Brian Lockhart,Frédéric Colland,John A. Hickman,Andrew W. Roberts,David C.S. Huang,David C.S. Huang,Andrew H. Wei,Andrew H. Wei,Andreas Strasser,Andreas Strasser,Guillaume Lessene,Guillaume Lessene,Olivier Geneste +66 more
TL;DR: It is demonstrated that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.
Journal ArticleDOI
Some case studies on application of "r(m)2" metrics for judging quality of quantitative structure-activity relationship predictions: emphasis on scaling of response data.
TL;DR: The present study reports that the web application can be easily used for computation of rm2 metrics provided observed and QSAR‐predicted data for a set of compounds are available and scaling of response data is recommended prior to rm2 calculation.
Journal ArticleDOI
Mcl-1 is a potential therapeutic target in multiple types of cancer.
TL;DR: Inhibition of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible to apoptosis and provide an opportunity to combat several types of cancers.
Journal ArticleDOI
MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain.
TL;DR: The naturally occurring MCL-1S variant represents a new proapoptotic BH3 domain-only protein capable of dimerizing with the antiapoptotics of the myeloid cellleukemia-1 gene.
Journal ArticleDOI
Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design
Anders Friberg,Dominico Vigil,Bin Zhao,R. Nathan Daniels,Jason P. Burke,Pedro M. Garcia-Barrantes,DeMarco V. Camper,Brian A. Chauder,Taekyu Lee,Edward T. Olejniczak,Stephen W. Fesik +10 more
TL;DR: The discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design and detailed information about the molecular recognition of small-molecule ligands binding M cl-1 is described.