Small-molecule crystal structures as a structural basis for drug design

1995 ◽  
Vol 51 (4) ◽  
pp. 407-417 ◽  
Author(s):  
C. Pascard
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Structural Basis

scholarly journals Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939

2012 ◽  
Vol 68 (2) ◽  
pp. 115-118 ◽  
Author(s):  
Christina A. Kirby ◽  
Atwood Cheung ◽  
Aleem Fazal ◽  
Michael D. Shultz ◽  
Travis Stams
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Donor Site ◽  
Structure Based Drug Design ◽  
Crystallization System ◽  
Tankyrase 1

The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD+donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1–PJ34 crystallization system has the NAD+donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1–PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.

scholarly journals Selective binding of small molecules to Vibrio cholerae DsbA offers a starting point for the design of novel antibacterials

2021 ◽  
Author(s):  
Geqing Wang ◽  
Biswaranjan Mohanty ◽  
Martin Williams ◽  
Bradley Doak ◽  
Rabeb Dhouib ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Crystal Structures ◽  
Small Molecule ◽  
Sodium Taurocholate ◽  
Structural Basis ◽  
Human Pathogens ◽  
X Ray ◽  
X Ray Crystallography ◽  
Hydrophobic Groove ◽  
Starting Point

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli. Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal that DsbA enzymes share a similar fold, however, the hydrophobic groove adjacent to the active site, which is implicated in substrate binding, is shorter and flatter in the structure of V. cholerae DsbA (VcDsbA) compared to E. coli DsbA (EcDsbA). The flat and largely featureless nature of this hydrophobic groove is challenging for the development of small molecule inhibitors. Using fragment-based screening approaches, we have identified a novel small molecule, based on the benzimidazole scaffold, that binds to the hydrophobic groove of oxidized VcDsbA with a KD of 446 ± 10 µM. The same benzimidazole compound has ~8-fold selectivity for VcDsbA over EcDsbA and binds to oxidized EcDsbA, with KD > 3.5 mM. We generated a model of the benzimidazole complex with VcDsbA using NMR data but were unable to determine the structure of the benzimidazole bound EcDsbA using either NMR or X-ray crystallography. Therefore, a structural basis for the observed selectivity is unclear. To better understand ligand binding to these two enzymes we crystallized each of them in complex with a known ligand, the bile salt sodium taurocholate. The crystal structures show that taurocholate adopts different binding poses in complex with VcDsbA and EcDsbA, and reveals the protein-ligand interactions that stabilize the different modes of binding. This work highlights the capacity of fragment-based drug discovery to identify inhibitors of challenging protein targets. In addition, it provides a starting point for development of more potent and specific VcDsbA inhibitors that act through a novel anti-virulence mechanism.

scholarly journals Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains

2021 ◽  
Author(s):  
Karen T Elvers ◽  
Magdalena Lipka-Lloyd ◽  
Rebecca C Trueman ◽  
Benjamin David Bax ◽  
Youcef Mehellou
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Protein Kinase ◽  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Domain Specific ◽  
Wnk Kinases ◽  
And Oxidative Stress

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and Oxidative Stress Responsive 1 (OSR1) kinase are two serine/threonine protein kinase that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream With No Lysine Kinases (WNKs), facilitating their activation via phosphorylation. Thus, the inhibition of SPAK and OSR1 binding, via their CCT domains, to WNK kinases is a plausible strategy for inhibiting SPAK and OSR1 kinases. To facilitate structure-guided drug design of such inhibitors, we expressed and purified human SPAK and OSR1 CCT domains and solved their crystal structures. We also employed a biophysical strategy and determined the affinity of SPAK and OSR1 CCT domains to an 18-mer peptide derived from WNK4. Together, the crystal structures and affinity data reported herein provide a robust platform to facilitate the design of CCT domain specific small molecule inhibitors of SPAK-activation by WNK kinases, potentially leading to new improved treatments for hypertension and ischemic stroke.

Jak3 Kinase Domain Crystal Structures and Implications for Jak-Specific Drug Design.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 69-69 ◽  
Author(s):  
Titus J. Boggon
Keyword(s):  
Crystal Structure ◽  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Severe Combined Immunodeficiency ◽  
Kinase Domain ◽  
Crystal Forms ◽  
Jak Kinase ◽  
Catalytic Cleft

Abstract Janus (Jak) family non-receptor tyrosine kinases are critical for appropriate signaling of many growth factors and cytokines. The four vertebrate Jak kinase family members demonstrate differential receptor cytoplasmic tail binding associations and transduce discrete signals on extracellular binding of ligand to the transmembrane cytokine or growth factor receptor. On ligand binding, a rapid tyrosine phosphorylation mediated signaling cascade is initiated, culminating in translocation of cytosolic latent transcription factors, signal transducer and activator of transcription (Stat) proteins, to the nucleus and targeted activation of transcription. Dysregulation of this Jak-mediated signaling pathway is documented in a number of hematological diseases: Improper upregulation of Jak activity is seen in certain hematological malignancies [1] and inability to appropriately transduce signals from the common gamma chain, γc, through Jak3 is responsible for approximately 60% of human severe combined immunodeficiency cases [2]. In addition, Jak2 point mutation V617F is frequently documented in myeloproliferative disorders including polycythemia vera; this activating mutation may disrupt an autoinhibited conformation [3]. Therapies targeting restraint of Jak family tyrosine kinase activity may be useful for treating inappropriate activation of Jak signaling cascades or for suppressing the immune response. Advances towards structure-directed drug design of Jak-specific inhibitors were made recently with solution of the Jak3 kinase domain X-ray crystal structure [4], representing the first three-dimensional structural data for any portion of the Jak family of tyrosine kinases. Here three further crystal structures of the kinase domain of Jak3 are presented: an improved resolution co-crystal structure with staurosporine analog AFN-941 and two crystal forms of Jak3 kinase domain in complex with the kinase inhibitor small molecule compound QAD-409. Comparisons between these three solved Jak3 kinase domain crystal structures illustrate conformational flexibility between the kinase domain lobes and in the area of the catalytic cleft. Further structure analysis is also presented documenting in silico modeling of the binding of small molecule CP-690,550 [5] to the different Jak3 kinase domain crystal forms. Potential binding conformations of this inhibitor to the Jak3 kinase domain are suggested with one highly scored binding conformation predicted for all crystal forms. The crystal structures and modeling studies presented further define the extent of the Jak kinase catalytic cleft, demonstrate conformational plasticity in the active conformation Jak3 kinase domain and will aid the design of higher specificity Jak inhibitors.

Crystal structures of Magnaporthe oryzae trehalose-6-phosphate synthase (MoTps1) suggest a model for catalytic process of Tps1

2019 ◽  
Vol 476 (21) ◽  
pp. 3227-3240 ◽  
Author(s):  
Shanshan Wang ◽  
Yanxiang Zhao ◽  
Long Yi ◽  
Minghe Shen ◽  
Chao Wang ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Magnaporthe Oryzae ◽  
Structural Information ◽  
Complex Structure ◽  
Critical Role ◽  
Catalytic Process ◽  
Structural Basis ◽  
Salt Bridges ◽  
Terminal Domain

Trehalose-6-phosphate (T6P) synthase (Tps1) catalyzes the formation of T6P from UDP-glucose (UDPG) (or GDPG, etc.) and glucose-6-phosphate (G6P), and structural basis of this process has not been well studied. MoTps1 (Magnaporthe oryzae Tps1) plays a critical role in carbon and nitrogen metabolism, but its structural information is unknown. Here we present the crystal structures of MoTps1 apo, binary (with UDPG) and ternary (with UDPG/G6P or UDP/T6P) complexes. MoTps1 consists of two modified Rossmann-fold domains and a catalytic center in-between. Unlike Escherichia coli OtsA (EcOtsA, the Tps1 of E. coli), MoTps1 exists as a mixture of monomer, dimer, and oligomer in solution. Inter-chain salt bridges, which are not fully conserved in EcOtsA, play primary roles in MoTps1 oligomerization. Binding of UDPG by MoTps1 C-terminal domain modifies the substrate pocket of MoTps1. In the MoTps1 ternary complex structure, UDP and T6P, the products of UDPG and G6P, are detected, and substantial conformational rearrangements of N-terminal domain, including structural reshuffling (β3–β4 loop to α0 helix) and movement of a ‘shift region' towards the catalytic centre, are observed. These conformational changes render MoTps1 to a ‘closed' state compared with its ‘open' state in apo or UDPG complex structures. By solving the EcOtsA apo structure, we confirmed that similar ligand binding induced conformational changes also exist in EcOtsA, although no structural reshuffling involved. Based on our research and previous studies, we present a model for the catalytic process of Tps1. Our research provides novel information on MoTps1, Tps1 family, and structure-based antifungal drug design.

Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies

2020 ◽  
Vol 19 (16) ◽  
pp. 1920-1934
Author(s):  
Xylia Q. Peters ◽  
Thembeka H. Malinga ◽  
Clement Agoni ◽  
Fisayo A. Olotu ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Design Methods ◽  
Selective Inhibitors ◽  
Computer Aided Drug Design ◽  
Cellular Processes ◽  
Conventional Drug ◽  
Computer Aided ◽  
Tankyrase 1

Background: Tankyrases are known for their multifunctionalities within the poly(ADPribose) polymerases family and playing vital roles in various cellular processes which include the regulation of tumour suppressors. Tankyrases, which exist in two isoforms; Tankyrase 1 and 2, are highly homologous and an integral part of the Wnt β -catenin pathway that becomes overly dysregulated when hijacked by pro-carcinogenic machineries. Methods: In this review, we cover the distinct roles of the Tankyrase isoforms and their involvement in the disease pathogenesis. Also, we provide updates on experimentally and computationally derived antagonists of Tankyrase whilst highlighting the precedence of integrative computer-aided drug design methods towards the discovery of selective inhibitors. Results: Despite the high prospects embedded in the therapeutic targeting and blockade of Tankyrase isoforms, the inability of small molecule inhibitors to achieve selective targeting has remained a major setback, even until date. This explains numerous incessant drug design efforts geared towards the development of highly selective inhibitors of the respective Tankyrase isoforms since they mediate distinct aberrancies in disease progression. Therefore, considering the setbacks of conventional drug design methods, can computer-aided approaches actually save the day? Conclusion: The implementation of computer-aided drug design techniques in Tankyrase research could help complement experimental methods and facilitate ligand/structure-based design and discovery of small molecule inhibitors with enhanced selectivity.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

Sign in / Sign up

Export Citation Format

Share Document