We present perturbative fluorine scanning, a computational fluorine scanning approach using free-energy perturbation. This method can be applied to molecular dynamics simulations of a single compound and make predictions for the best binders out of numerous fluorinated analogues. We tested the method on nine test systems: renin, DPP4, menin, P38, factor Xa, CDK2, AKT, JAK2, and androgen receptor. The predictions were in excellent agreement with more rigorous alchemical free-energy calculations and in good agreement with experimental data for most of the test systems. However, the agreement with experiment was very poor in some of the test systems, and this highlights the need for improved force fields in addition to accurate treatment of tautomeric and protonation states. The method is of particular interest due to the wide use of fluorine in medicinal chemistry to improve binding affinity and ADME properties. The promising results on this test case suggest that perturbative fluorine scanning will be a useful addition to the available arsenal of free-energy methods.

26 Sep 2016·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening

Q2 · CHEMISTRY

Article

Author: Luo, Cheng ; Liu, Rongfeng ; Xing, Jing ; Yue, Liyan ; Wang, Yulan ; Luo, Xiaomin ; Xu, Yuan ; Shi, Zhe ; Jiang, Hualiang ; Chen, Kaixian ; Zheng, Mingyue ; Liu, Yu-Chih ; Chen, Zhifeng

Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 ± 0.12 μM and a KD of 14.70 ± 2.13 μM, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI50 values of 0.84 μM and 0.54 μM, respectively.

01 Jul 2015·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility

Q4 · MEDICINE

Article

Author: Gogliotti, Rocco D ; Stauffer, Shaun R ; Cierpicki, Tomasz ; Locuson, Charles W ; Han, Changho ; Daniels, J Scott ; Grembecka, Jolanta ; Senter, Timothy ; Morrison, Ryan ; Lindsley, Craig W

A series of substituted hydroxymethyl piperidine small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) are described. Initial members of the series showed good inhibitory disruption of the menin-MLL1 interaction but demonstrated poor physicochemical and DMPK properties. Utilizing a structure-guided and iterative optimization approach key substituents were optimized leading to inhibitors with cell-based activity, improved in vitro DMPK parameters, and improved half-lives in rodent PK studies leading to MLPCN probe ML399. Ancillary off-target activity remains a parameter for further optimization.

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	Preclinical	United States	Vanderbilt University Medical Center	28 Feb 2013

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