Investigation of Family 18 Chitinases and Inhibitors by Computer-Aided Approaches

Abstract

Chitinases belong to family 18 glycosyl hydrolases that can hydrolyze chitin by cleaving β-1,4-glycosidic bond, and are at key points in the life cycles of organism. The inhibitors of chitinases not only have chemotherapeutic potential against fungi, insects, but also hold anti-inflammatory efficacy against asthma and allergic disease in human. This review summarizes the structural characters of chitinases, the proposed catalytic mechanism, furthermore, also gives descriptions of currently existing inhibitors. In addition, computational studies of the interaction modes of chitinases with different inhibitors and substrates, as well as the inhibitor design of chitinases, are summarized so as to obtain an overall understanding for chitinases.Keywords: Chitinases, chitinase inhibitors, computer-aided approach. CHITIN AND CHITINASESChitin (C 8 H 13 O 5 N) n (shown in Fig. 1a), a linear insoluble homopolymer of N-acetyl-D-glucosamine (GlcNAc), is the second most abundant polysaccharide on the earth next to the cellulose [1, 2] and has been found in a wide range of organism, including bacteria, fungi, insects, and viruses [3][4][5].Accumulation of chitin in an organism is modulated by chitin synthase-mediated biosynthesis and chitinases-mediated hydrolytic degradation [6]. Since chitin synthases have become an ideal target for the development of pesticides and fugicides in agriculture, the design of chitin synthase's inhibitors has attracted much more attention [7,8]. Recently, some chitin synthase inhibitors have been successfully designed and synthesized in the group of Dr. Qing Yang [6,9], and these synthesized inhibitors were claimed to be novel potential agents due to their bioactivities. Chitinases (EC 3.2.1.14) play a key role in hydrolyzing β-1,4-glycosidic bond of the chitin into low molecular weight, soluble oligomers of GlcNAc [10,11]. Chitinases are currently classified into two different families of glycosyl hydrolases, namely family 18 and family 19 [12][13][14], and this review mainly focuses on family 18 chitinases studies, information available from their three-dimensional structures and the biochemistry of reaction. Chitinases are also widespread, and perform different functions in the different organism [15][16][17][18][19][20]. Although chitin does not exist in mammals, human chitinase family members, such as acidic mammalian chitinase (AMCase), have also been described in previous Therefore, the design of chitinases inhibitors is of great interest. The well-known inhibitor allosamidin (shown in Fig. 1b) is the most potent broad-spectrum inhibitor of chitinases. It inhibits chitinases by mimicing the reaction intermediate [24], but unfortunately, the synthesis of allosamidin and its derivatives are very difficult and expensive, which makes it a less suitable candidate targating a common chemotherapeutical therapy [25]. Izumida et al. found another effective chitinases inhibitor, the cyclic dipeptide [cyclo-(L-Arg-D-pro)] CI-4 (shown in Fig. 1c) [26]. CI-4 shows relatively weak inhibition ...

Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors

“…Recently, structure-based virtual screening (SBVS) and fragment-based drug discovery have been rapidly developed as effective methods to identify hits. − Having characterized the crystal structures of chitinase as well as the cocrystal structures of enzyme–inhibitor complexes, their structure–activity relationships have been revealed, and SBVS has been used to identify potential chitinase inhibitors. − A typical GH18 chitinase usually possesses a long, cleftlike catalytic domain with multiple binding subsites labeled as +2, + 1, −1, −2, −3, −4, and −5, and catalysis always occurs between the subsites +1 and −1 . Not surprisingly, chitinase structural-biology studies have offered valuable opportunities for the rational design of new and bioavailable inhibitors via in silico analysis …”

Identification of Novel and Safe Fungicidal Molecules against Fusarium oxysporum from Plant Essential Oils: In Vitro and Computational Approaches

“…The use of computational approaches, of computer-aided drug design (CADD), is getting popular in pesticide development research and industry from the end of the last decade [ 22 ]. The increasing rate of pesticide resistance development, human health hazards, and environment pollution by synthetic pesticides tends to an urge of development of novel effective and safe molecules for agricultural industry.…”

“…The pesticide development in the wet labs is a tedious expensive and time-consuming job. The pipeline of techniques used in CADD is based on the initial screening of chemical compounds which leads to narrowing down the dataset consisting of the effective and potential molecules [ 22 ]. This regime changes in pesticide development from conventional methods to combining with computational technology have been proved a progressive trend [ 23 ].…”