Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition

Englert, L.; Silber, Katrin; Steuber, H.; Brass, Sascha; Over, Bjӧrn; Gerber, Hans‐Dieter; Heine, A.; Diederich, Wibke E.; Klebe, G.

doi:10.1002/cmdc.201000084

Cited by 27 publications

(21 citation statements)

References 52 publications

(53 reference statements)

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“…For example, if a contiguously connected water network ruptures like in TLN-1, an enthalpic loss and an entropic gain are experienced relative to TLN-2. [26] The loss of the hydrogen bonds caused by this rupture allows the system to activate and thus distribute energy over more degrees of freedom. The displacement of ordered water molecules can be entropically favorable.…”

Section: Methodsmentioning

confidence: 99%

“…[16][17][18] The enzyme has been frequently used as a surrogate [19][20][21][22][23] for other metalloenzymes against which new drugs are developed, and served as a model system to test ideas [24,25] and new methodological concepts. [26] TLN was one of the first crystallographically investigated metalloproteases [27,28] and its catalytic zinc ion is coordinated by His142, His146, and Glu166. The adjacent S 1 subsite is rather nonspecific and accommodates hydrophobic ligand portions.…”

mentioning

confidence: 99%

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Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin

et al. 2013

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Dedicated to Professor Jack D. Dunitz on the occasion of his 90th birthdayThe hydrophobic effect is viewed as the driving force for the aggregation of nonpolar substances with extended lipophilic molecular surfaces in aqueous solution through the exclusion of water molecules from the formed interfaces. [1,2] It is usually quoted to explain why an oil/water mixture spontaneously separates, why soluble proteins fold with a hydrophobic core and a hydrophilic outer surface, [3,4] why membrane components assemble as lipid bilayers and micelles, why membrane proteins are accommodated in membrane segments, and why small molecules associate in protein binding pockets with mutual burial of hydrophobic surfaces. [5] In the latter instance, it is a general strategy in medicinal chemistry to improve protein-ligand binding by increasing the ligands hydrophobic surface which becomes buried in hydrophobic pockets of the target protein. In all cases, the hydrophobic effect is considered to be the major force of association. On the molecular level, this phenomenon is commonly attributed to the displacement of water molecules arranged around the hydrophobic surfaces, and entropic effects are made responsible to drive this association. The entropic profile is related to changes in the degree of ordering and the dynamic properties of the water molecules, which are assumed to be more disordered in the bulk water phase relative to where they were located prior to being displaced upon hydrophobic association. Recent studies have demonstrated, however, that hydrophobic interactions can originate either from enthalpyor entropy-driven binding, making simple explanations often presented for the hydrophobic effect insufficient. [6][7][8][9][10][11][12] Also in computational design tools the handling of explicit water molecules has received increasing recognition. Tools such as WaterMap and Szmap [13,14] try to take into account water structures in drug design and the properties of individual water molecules are discussed in terms of enthalpy and entropy.In order to obtain a better understanding of the hydrophobic effect on the molecular level and its role in proteinligand binding, we embarked on a systematic study using thermolysin (TLN) as a model system. [6] This thermostable bacterial zinc metalloprotease from Bacillus thermoproteolyticus exhibits three specificity pockets of predominantly hydrophobic nature (Scheme 1). It has been considered a prototype for the entire class of enzymes [15] owing to its highly conserved active-site architecture, despite remarkable sequence differences to other zinc proteases. Potent TLN inhibitors are often designed as transition-state analogues. [16][17][18] The enzyme has been frequently used as a surrogate [19][20][21][22][23] for other metalloenzymes against which new drugs are developed, and served as a model system to test ideas [24,25] and new methodological concepts. [26] TLN was one of the first crystallographically investigated metalloproteases [27,28] and its catalytic zinc ion is coordinated ...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin

et al. 2013

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“…Both, compounds with a high total score and a high normalized score were carried forward for visual inspection. Interestingly, all compounds that showed any IspE inhibition (Table 1) were selected based on the latter criteria and were in the fragment-like space making this exercise yet another success story of fragment-based virtual screening [25], [47], [48], [49], [50], [51], [52].…”

Section: Discussionmentioning

confidence: 99%

IspE Inhibitors Identified by a Combination of In Silico and In Vitro High-Throughput Screening

Tidten-Luksch¹,

Grimaldi²,

Torrie³

et al. 2012

PLoS ONE

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CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens.

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“…These include, among others, the discovery of ligands of thrombin [55], inosine 5'-monophosphate dehydrogenase [56], L-xylose reductase [57], aurora A kinase [58], dipeptidyl peptidase IV [59], Ampc -lactamase [60], anthrax edema factor [61], macrophage inhibitory factor [62], thermolysine [63], 6-phosphogluconate dehydrogenase [64], indoleamine 2,3-dioxygenase [65,66], NF-B inducing kinase [67], Heat Shock Protein 90 [68], and PIM1 kinase [69]. A summary of the biological targets and the used docking software is given in Table 2.…”

Section: Dockingmentioning

confidence: 99%

Computational Tools for In Silico Fragment-Based Drug Design

Mortier¹,

Rakers²,

Frédérick³

et al. 2012

CTMC

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Fragment-based strategy in drug design involves the initial discovery of low-molecular mass molecules. Owing to their small-size, fragments are molecular tools to probe specific sub-pockets within a protein active site. Once their interaction within the enzyme cavity is clearly understood and experimentally validated, they represent a unique opportunity to design potent and efficient larger compounds. Computer-aided methods can essentially support the identification of suitable fragments. In this review, available tools for computational drug design are discussed in the frame of fragmentbased approaches. We analyze and review (i) available commercial fragment libraries with respect to their properties and size, (ii) computational methods for the construction of such a library, (iii) the different strategies and software packages for the selection of the fragments with predicted affinity to a given target, and (iv) tools for the in silico linkage of fragments into an actual high-affinity lead structure candidate.

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Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition

Cited by 27 publications

References 52 publications

Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin

Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin

IspE Inhibitors Identified by a Combination of In Silico and In Vitro High-Throughput Screening

Computational Tools for In Silico Fragment-Based Drug Design

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