Editorial

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Foreword: Pacific Fragments

by Daniel A. Erlanson

Molecules 2016, 21(7), 926; https://doi.org/10.3390/molecules21070926 - 16 Jul 2016

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Abstract

Pacific, which is derived from the Latin pac, means peaceful. [...] Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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Research

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Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments

by Qingwen Zhang, Xuejin Zhang and Qidong You

Molecules 2016, 21(7), 879; https://doi.org/10.3390/molecules21070879 - 16 Jul 2016

Cited by 6 | Viewed by 7816

Abstract

The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP [...] Read more.

The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phenylaminopyrimidine (PAP) and unsymmetrically disubstituted urea as two fragments that are frequently presented in FDA-approved protein kinase inhibitors. We therefore defined PAP and unsymmetrically disubstituted urea as privileged fragments for kinase drug discovery. A pharmacophore for type II inhibitors, 4-phenylaminopyrimidine urea (4-PAPU), was assembled based upon these privileged fragments. Lead compound SI-046 with BRAF V600E inhibitory activity comparable to the template compound sorafenib was in turn obtained through preliminary structure–activity relationship (SAR) study. Molecular docking suggested that SI-046 is a bona fide type II kinase inhibitor binding to the structurally validated “classical DFG-out” conformation of BRAF V600E. Our privileged fragments-based approach was shown to efficiently deliver a bona fide type II kinase inhibitor lead. In essence, the theme of this article is to showcase the strategy and rationale of our approach. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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9188 KiB

Open AccessArticle

An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor

by Ram B. Khattri, Daniel L. Morris, Caroline M. Davis, Stephanie M. Bilinovich, Andrew J. Caras, Matthew J. Panzner, Michael A. Debord and Thomas C. Leeper

Molecules 2016, 21(7), 846; https://doi.org/10.3390/molecules21070846 - 16 Jul 2016

Cited by 6 | Viewed by 8070

Abstract

Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and ¹⁵N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental [...] Read more.

Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and ¹⁵N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins—a heretofore untapped reservoir for antibiotic agents. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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Review

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Native Mass Spectrometry in Fragment-Based Drug Discovery

by Liliana Pedro and Ronald J. Quinn

Molecules 2016, 21(8), 984; https://doi.org/10.3390/molecules21080984 - 28 Jul 2016

Cited by 52 | Viewed by 10806

Abstract

The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein–ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established [...] Read more.

The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein–ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established utility for fragment-based drug discovery (FBDD). Native MS has the capability to directly detect weak ligand binding to proteins, to determine stoichiometry, relative or absolute binding affinities and specificities. Native MS can be used to delineate ligand-binding sites, to elucidate mechanisms of cooperativity and to study the thermodynamics of binding. This review highlights key attributes of native MS for FBDD campaigns. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery

by Renjie Huang and Ivanhoe K. H. Leung

Molecules 2016, 21(7), 910; https://doi.org/10.3390/molecules21070910 - 16 Jul 2016

Cited by 33 | Viewed by 13454

Abstract

Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The [...] Read more.

Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique. Such information is useful as a starting point to guide further organic synthesis of novel protein ligands and enzyme inhibitors. This review uses literature examples to discuss the practicalities of applying this method to inhibitor discovery, in particular, the set-up of the combinatorial library, the reversible reactions that may be employed, and the choice of detection methods to screen protein ligands from a mixture of reversibly forming molecules. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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Applications of ¹⁹F-NMR in Fragment-Based Drug Discovery

by Raymond S. Norton, Eleanor W. W. Leung, Indu R. Chandrashekaran and Christopher A. MacRaild

Molecules 2016, 21(7), 860; https://doi.org/10.3390/molecules21070860 - 16 Jul 2016

Cited by 69 | Viewed by 11242

Abstract

¹⁹F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the [...] Read more.

¹⁹F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the target protein, useful information can be obtained on not only the binding pose but also the dynamics of ligand-protein interactions. These applications of ¹⁹F-NMR will be illustrated in this review with studies from our fragment-based drug discovery campaigns against protein targets in parasitic and infectious diseases. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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2966 KiB

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Process of Fragment-Based Lead Discovery—A Perspective from NMR

by Rongsheng Ma, Pengchao Wang, Jihui Wu and Ke Ruan

Molecules 2016, 21(7), 854; https://doi.org/10.3390/molecules21070854 - 16 Jul 2016

Cited by 25 | Viewed by 9824

Abstract

Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein–protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power [...] Read more.

Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein–protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein–ligand structure model generation. For weak binders, the initial hit-to-lead evolution can be guided by structural information retrieved from NMR spectroscopy, including chemical shift perturbation, transferred pseudocontact shifts, and paramagnetic relaxation enhancement. This perspective examines structure-guided optimization from weak fragment screening hits to potent leads for challenging PPI targets. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents

by Roxanne P. Smith, Jason J. Paxman, Martin J. Scanlon and Begoña Heras

Molecules 2016, 21(7), 811; https://doi.org/10.3390/molecules21070811 - 16 Jul 2016

Cited by 48 | Viewed by 8882

Abstract

Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways [...] Read more.

Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways are potential targets for the development of antimicrobial agents because they play a central role in bacterial pathogenesis. In particular, the DsbA/DsbB system catalyses disulfide bond formation in a wide array of virulence factors, which are essential for many pathogens to establish infections and cause disease. These redox enzymes are well placed as antimicrobial targets because they are taxonomically widespread, share low sequence identity with human proteins, and many years of basic research have provided a deep molecular understanding of these systems in bacteria. In this review, we discuss disulfide bond catalytic pathways in bacteria and their significance in pathogenesis. We also review the use of different approaches to develop inhibitors against Dsb proteins as potential anti-virulence agents, including fragment-based drug discovery, high-throughput screening and other structure-based drug discovery methods. Full article

(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)

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