Binding Modes of Small‐Molecule Inhibitors to the EED Pocket of PRC2

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of Bacillus anthracis protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydrosolubility and tested their ability to dock the relevant binding cavity. The highest-ranking docking hits were then subjected to 125 ns-long simulations to ascertain the stability of the binding modes. Several of the potential candidates performed quite disappointingly , but two molecules showed very stable binding modes throughout the complete simulations. Besides the identification of these two promising leads, these molecular dynamics simulations allowed the discovery of several insights that shall prove useful in the further improvement of these candidate towards higher potency and stability.

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Probing Binding Modes of Small Molecule Inhibitors to the Polo-Box Domain of Human Polo-like Kinase 1

ACS Medicinal Chemistry Letters ◽

10.1021/ml100020e ◽

2010 ◽

Vol 1 (3) ◽

pp. 110-114 ◽

Cited By ~ 42

Author(s):

Chenzhong Liao ◽

Jung-Eun Park ◽

Jeong K. Bang ◽

Marc C. Nicklaus ◽

Kyung S. Lee

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Binding Modes

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Binding ofN-substituted pyrrole derivatives to HIV-1 gp41

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633614500187 ◽

2014 ◽

Vol 13 (02) ◽

pp. 1450018 ◽

Cited By ~ 2

Author(s):

Kunzhong Song ◽

Ju Bao ◽

Yueming Sun ◽

John Z. H. Zhang

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Computational Study ◽

Binding Modes ◽

Binding Mechanism ◽

Free Energies ◽

Theoretical Understanding ◽

Pyrrole Derivatives ◽

Immunodeficiency Virus ◽

Hiv 1

Developing small molecule inhibitors of human immunodeficiency virus type 1 (HIV-1) fusion has attracted significant interest. Recently, Jiang have reported several natural and synthetic N -substituted pyrrole derivatives targeting gp41 that are experimentally shown to inhibit cell–cell fusion in the low micromolar range. In order to help gain insight on the binding mechanism, we carried out computational study to help identify possible binding modes and to characterize structures of binding complexes. Detailed gp41-molecule binding interactions and free energies of binding are obtained through molecular dynamics (MD) simulation and MM-PBSA calculation. Specific molecular interactions in the gp41-inhibitor complexes are identified. Current computational study complements the corresponding experimental investigation and provides theoretical understanding on the binding mechanism which is helpful for further refinement of small molecule inhibitors of gp41.

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Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1

Pure and Applied Chemistry ◽

10.1351/pac-con-10-10-29 ◽

2011 ◽

Vol 83 (3) ◽

pp. 723-731 ◽

Cited By ~ 14

Author(s):

Paul H. Bernardo ◽

Thirunavukkarasu Sivaraman ◽

Kah-Fei Wan ◽

Jin Xu ◽

Janarthanan Krishnamoorthy ◽

...

Keyword(s):

B Cell ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Cell Lymphoma ◽

Myeloid Cell ◽

B Cell Lymphoma ◽

Binding Modes ◽

Cell Leukemia ◽

Compound Library

A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu-Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.

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