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Niu Huang's Lab





Novel “pairs” of drugs possessing pharmacological synergies could be encapsulated into polymeric micelles and exert superb therapeutic effects in vivo upon intravenous administration, with the prerequisite that the micelles remain stable. NADP(H) quinone oxidoreductase 1 (NQO1) inhibitors, such as β-lapachone (LPC) and tanshinone IIA (THA) are structurally and pharmacologically similar molecules that are both poorly water soluble, crystallize extremely fast, and demonstrate synergistic anticancer effect when used together with paclitaxel (PTX). However, when co-encapsulated with PTX in poly (ethylene glycol)-b-poly (D, L-lactic acid) (PEG-PLA) micelles, only PTX/LPC but not PTX/THA pair yield satisfactory colloidal stability. To reveal the molecular mechanism contributing to the colloidal stability of the co-encapsulated micelles, we investigated the molecular interactions of PTX/LPC and PTX/THA, through both experimental methods (crystallization kinetics, 13C-NMR) and molecular dynamic simulation. We observed that PTX was capable of inhibiting LPC but not THA crystallization both in aqueous environment and in solid state, which could be attributed to the strong hetero-intermolecular interactions (π-π, H-bonding) between LPC and PTX, which disrupted the homo-intermolecular interactions between LPC molecules and thus formed a favorable miscible binary system. In comparison, the lack of a strong PTX/THA interaction left the strong THA/THA stacking interaction undisturbed and the fast THA crystallization tendency unrestrained. We conclude that the intermolecular interactions, i.e., the “pharmaceutical synergy”, between the co-encapsulated drugs critically control the colloidal stability of polymeric micelles, therefore shall be evaluated when design co-encapsulated drug delivery systems for optimal therapeutic benefits.
Intermolecular interactions between co-encapsulated drugs inhibit drug crystallization and enhance colloidal stability of polymeric micelles.

Classic papers->Medicinal Chemistry

Posted by admin on June 16, 2017
Posted in news 

 Classic papers
Title Author Cited
RA Friesner, RB Murphy, MP Repasky… – Journal of medicinal …, 2006
GL Warren, CW Andrews, AM Capelli… – Journal of medicinal …, 2006
N Huang, BK Shoichet, JJ Irwin – Journal of medicinal chemistry, 2006
W Sherman, T Day, MP Jacobson… – Journal of medicinal …, 2006
J Wang, SM Soisson, K Young, W Shoop, S Kodali… – Nature, 2006
K Ding, Y Lu, Z Nikolovska-Coleska… – Journal of medicinal …, 2006
M Matsumoto, H Hashizume, T Tomishige… – PLoS Med, 2006
No profilesNo profiles
HA Overton, AJ Babbs, SM Doel, MCT Fyfe… – Cell …, 2006
No profilesNo profiles
MS Karthikeyan, DJ Prasad, B Poojary… – … & medicinal chemistry, 2006
M Whiting, J Muldoon, YC Lin… – Angewandte Chemie …, 2006
Dates and citation counts are estimated and are determined automatically by a computer program.

CryoEM structure of yeast cytoplasmic exosome complex.

Posted by admin on December 12, 2016
Posted in news 

CryoEM structure of yeast cytoplasmic exosome complex.

Jun-Jie Liu1,2,*, Chu-Ya Niu1,*, Yao Wu3,*, Dan Tan3, Yang Wang1, Ming-Da Ye1, Yang Liu2,4, Wenwei Zhao4, Ke Zhou5, Quan-Sheng Liu5, Junbiao Dai6, Xuerui Yang4, Meng-Qiu Dong3, Niu Huang3 and Hong-Wei Wang1

jcim Discovery of 2-Acylaminothiophene-3-Carboxamides as Multitarget Inhibitors for BCR-ABL Kinase and Microtubules. Cao R1, Wang Y1, Huang N1. 1National Institute of Biological Sciences, Beijing , No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China. Abstract The emergence of drug resistance of the BCR-ABL kinase inhibitor imatinib, especially toward the T315I gatekeeper mutation, poses a great challenge to targeted therapy in treating chronic myeloid leukemia (CML) patients. To discover novel inhibitors against drug-resistant CML bearing T315I mutation, we applied a physics-based hierarchical virtual screening approach to dock a large chemical library against ATP binding pockets of both wild-type (WT) and T315I mutant ABL kinases in a combinatorial fashion. This strategy automatically resulted in 87 compounds satisfying structural and energetic criteria of both WT and T315I mutant kinases. Among them, nine compounds, which share a common thiophene-based scaffold and adopt similar binding poses, were chosen for experimental testing and one of them was shown to have low micromolar inhibition activities against both WT and mutant ABL kinases. Structure-activity relationship analysis with a series of structural modifications based on 2-acylaminothiophene-3-carboxamide scaffold supports our predicted binding mode. Interestingly, the same chemical scaffold was also enriched in our previous virtual screening campaign against colchicine site of microtubules using the same computational protocol, which suggests our virtual screening strategy is capable of discovering small-molecule ligands targeting distinct protein binding sites without sharing any sequential and structural similarity. Furthermore, the multitarget inhibition activity of this class of compounds was assessed in cellular experiments. We expect that the 2-acylaminothiophene-3-carboxamide scaffold may serve as a promising starting point for developing multitarget inhibitors in cancer treatment by targeting both kinases and microtubules.