High throughput screening under zinc-database and synthesis a dialkylphosphinic acid as a potential Kari inhibitor

Article abstract of DOI:10.1080/10426500701807897

A novel phosphorus derivative was synthesized through HTVS. The title compounds were confirmed by MS, 1H NMR, 31P NMR. The DOCK was also studied. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701807897

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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High Throughput Screening
Under Zinc-Database and
Synthesis a Dialkylphosphinic
Acid as a Potential Kari
Inhibitor
Xing-Hai Liu a , Pei-Quan Chen a , Wan-Cheng Guo a
Su-Hua Wang a & Zheng-Ming Li a
,
a The Research Institute of Elemento-Organic
Chemistry, The State-Key Laboratory of Elemento-
Organic Chemistry, National Pesticide Engineering
Research Center , Nankai University , Tianjin, China
Published online: 20 Jun 2008.
To cite this article: Xing-Hai Liu , Pei-Quan Chen , Wan-Cheng Guo , Su-Hua Wang &
Zheng-Ming Li (2008) High Throughput Screening Under Zinc-Database and Synthesis a
Dialkylphosphinic Acid as a Potential Kari Inhibitor, Phosphorus, Sulfur, and Silicon and
the Related Elements, 183:2-3, 775-778, DOI: 10.1080/10426500701807897
To link to this article: http://dx.doi.org/10.1080/10426500701807897
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Phosphorus, Sulfur, and Silicon, 183:775–778, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701807897
High Throughput Screening Under Zinc-Database
and Synthesis a Dialkylphosphinic Acid
as a Potential Kari Inhibitor
Xing-Hai Liu, Pei-Quan Chen, Wan-Cheng Guo,
Su-Hua Wang, and Zheng-Ming Li
The Research Institute of Elemento-Organic Chemistry, The State-Key
Laboratory of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, Nankai University, Tianjin, China
A novel phosphorus derivative was synthesized through HTVS. The title compounds
were confirmed by MS, 1H NMR, 31P NMR. The DOCK was also studied.
Keywords DOCK; KARI; phosphorus derivatives; synthesis
1. INTRODUCTION
Ketol-acid reductoisomerase (KARI; EC 1.1.1.86)1 is an attractive tar-
get for argochemical discovery because it catalyzes the second impor-
tant step in the biosynthesis of the branched chain amino acids that
exist in higher plants only and not in animals. Thus, it is an ideal tar-
get from which to design nontoxic KARI-inhibitors as potential novel
herbicides. The reaction catalyzed by KARI is shown in Figure 1.
In particular, as high throughput screening considerably increased
the numbers of new chemical entities to be studied, the expectations
to find new bio-active molecules among these compounds were high
at the beginning. However, high throughput screenings (HTS) yielded
so far the expected success, and therefore virtual screening approaches
emerged and largely evolved. Today, high throughput virtual screening
(HTVS) is useful in argochemical innovation.
This work was funded by the National Basic Research Program of China (No.
2003CB114406), National Natural Science Foundation Key Project of China (No.
20432010), and The High Performance Computing Project of Tianjin Ministry of Science
and Technology of China (No. 043185111-5).
Address correspondence to Zheng-ming Li, The Research Institute of Elemento-
Organic Chemistry, The State-Key Laboratory of Elemento-Organic Chemistry, Na-
tional Pesticide Engineering Research Center, Nankai University, Tianjin 300071, China.
E-mail:nkzml@vip.163.com; xhliu@mail.nankai.edu.cn
775

776
X.-H. Liu et al.
FIGURE 1 Reaction catalyzed by KARI.
2. METHODS AND EXPERIMENTS
2.1. HTVS
Based on the reported crystal structure of complexes of the en-
zyme KARI, 1000 new molecules were predicted with high affinity
for KARI from ZINC-database (Drug-Like) searching, using program
eHiTS.5 The computational flow chart for this study was shown as in
Figure 2. Among them, many compounds contain phosphorus struc-
tures. A dialkylphosphinic acid was noticed which is analogy of HOE
704 (Figure 1).
FIGURE 2 Computational and experimental flow chart for this study.

High Throughput Screening Under Zinc-Database
777
2.2. Synthesis
The dialkylphosphinic acid was synthesized according the reference6
(Scheme 1). The physical chemistry data were accordance with the
reference.
SCHEME 1 The synthesis route of the title compound.
3. RESULTS AND DISCUSSION
3.1. HTVS
A dialkylphosphinic acid was docked with KARI and estimated the
pKi = −5.235. The interaction pattern (Figures 3 and 4) between the
titled compound and KARI was same as IpOHA (Figure 1). The Mg2+
ions and the crystal water molecules, inhibitor in the active site are nec-
essary for constructing and maintaining the conformation of the active
FIGURE 3 Spinage KARI active site with title compound.

778
X.-H. Liu et al.
FIGURE 4 Superimposition of the docked modeled into the binding pocket
conformation.
site and thus the binding affinity of ligand or the enzymatic activity of
title compound and IpOHA in complex with spinage KARI.
3.2. Synthesis and Biological Activity
The synthesis route of the title compound is shown in the Scheme 1. The
method was not modified. The dialkylphosphinic acid was synthesized
for further bioassay experiments.
4. CONCLUSION
A new potential lead compound of KARI inhibitor was found by virtual
and laboratory screening for further optimization.
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