Prediction of Protein Three-dimensional Structures in Insertion and Deletion Regions: A Procedure for Searching Data Bases of Representative Protein Fragments Using Geometric Scoring Criteria

Fechteler, Till; Dengler, Uwe; Schomburg, Dietmar

doi:10.1006/jmbi.1995.0540

Cited by 111 publications

(78 citation statements)

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“…In the next step, 10 CCR5 intermediate models are generated using the Boltzmann-weighted randomized modeling procedure (Levitt, 1992). The insertions and deletions within the structure are handled using the procedure described by Fechteler et al (1995). Loops are modeled following a contact energy function that analyzes the list of candidates taking into account all atoms already modeled.…”

Section: Methodsmentioning

confidence: 99%

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

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In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of smallmolecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.Human immunodeficiency virus (HIV) enters the host cell via the interaction of the viral envelope protein gp160 and the receptor/coreceptors on host cell surface. The majority of primary HIV-1 strains use CCR5 as coreceptor (termed R5 virus), whereas some viruses are able to use another chemokine receptor, CXCR4, as coreceptor (termed X4 virus) or use both CCR5 and CXCR4 as coreceptors (termed R5X4 virus). Because CCR5 is the predominant coreceptor for clinical HIV isolates, and the normal physiology within the human genetic knockout population, CCR5 has become a very attractive target for anti-HIV therapy. A number of small molecule CCR5 antagonists have been identified that demonstrated potent antiviral effects both in cell culture and in clinical trials.TAK-779, a quaternary ammonium anilide, was the first small molecule CCR5 antagonist reported (Baba et al., 1999). This compound was terminated as a result of poor oral availability. Two structurally diverse followers TAK-220 and TAK-652 are both in clinical trials (Imamura et al., 2006;Seto et al., 2006). Several other small molecule CCR5 antagonists with good potency and/or pharmacological properties have also been reported by other pharmaceutical companies. These include SCH-C (SCH-351125), vicriviroc (VVC, SCH-D, SCH-417690), aplaviroc (APL, AK602, GW873140), and maraviroc (MVC, UK-427,857). SCH-C is an oximino-piperidino-piperidine amide (Palani et al., 2002) that showed potent antiviral activity in vivo. However, its clinical development was terminated as a result of HERG inhibitory activity. SCH-D is the next generation compound of SCH-C, which is in late stage clinical development. SCH-D showed better oral availability, potency, safety, and pharmacological properties than SCH-C Article, publication d...

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Section: Methodsmentioning

confidence: 99%

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Kondru

Zhang²,

Ji³

et al. 2007

Mol Pharmacol

174

189

View full text Add to dashboard Cite

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“…Docking Studies Between MyD88 and Mal. Structure modeling of the TIR domain of Mal was performed using the MyD88-TIR structure as a template on molecular operating environment (MOE) software (39,40). The docking simulation was performed on AutoDock without any specific restraints between the molecules as previously reported (24,41,42).…”

Section: Vector Preparationsmentioning

confidence: 99%

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

Ohnishi

Tochio

Kato

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

192

185

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“…To avoid deletions or insertions in conserved regions, the alignment was inspected and corrected manually if necessary. A series of 10 models was constructed with MOE, using a Boltzmann-weighted randomized procedure combined with specialized logic for the handling of sequence insertions and deletions (33,34). The model with the best packing quality function was selected for full-energy minimization.…”

Section: Methodsmentioning

confidence: 99%

Dialkylresorcinols as bacterial signaling molecules

Brameyer

Kresovic

Bode

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

127

108

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It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the wellknown AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell-cell communication system in the insect and human pathogen Photorhabdus asymbiotica. We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica. On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell-cell communication goes far beyond AHL signaling in nature.

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Prediction of Protein Three-dimensional Structures in Insertion and Deletion Regions: A Procedure for Searching Data Bases of Representative Protein Fragments Using Geometric Scoring Criteria

Cited by 111 publications

References 0 publications

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

Dialkylresorcinols as bacterial signaling molecules

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