scholarly journals Effects of inhibitors on Hsp90’s conformational dynamics, cochaperone and client interactions

2018 ◽  
Author(s):  
Sonja Schmid ◽  
Markus Götz ◽  
Thorsten Hugel
Keyword(s):  
Conformational Dynamics ◽  
Rational Drug Design ◽  
Hsp90 Inhibition ◽  
Allosteric Inhibitors ◽  
Central Target ◽  
Drug Candidates ◽  
Rational Drug ◽  
Kinetic Rate Constants ◽  
Opening And Closing

AbstractThe molecular chaperone and heat-shock protein Hsp90 has become a central target in anti-cancer therapy. Nevertheless, the effect of Hsp90 inhibition is still not understood at the molecular level, preventing a truly rational drug design. Here we report on the effect of the most prominent drug candidates, namely radicicol, geldanamycin, derivatives of purine and novobiocin, on Hsp90’s characteristic conformational dynamics and the binding of three interaction partners. Unexpectedly, the global opening and closing transitions are hardly affected by Hsp90 inhibitors. Instead, the conformational equilibrium, as well as the associated kinetic rate constants remain almost untouched. Moreover, we find no significant changes in the binding of the cochaperones Aha1 and p23 nor of the model substrate Δ131Δ. This holds true for both, competitive and allosteric inhibitors. Therefore, direct inhibition mechanisms, affecting only one molecular interaction, are unlikely. Based on our results, we speculate that the inhibitory action observed in vivo is caused by a combination of subtle effects, which can be used in the search for novel Hsp90 inhibition mechanisms.

scholarly journals 1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S411-S412
Author(s):  
Edward P Garvey ◽  
Andrew Sharp ◽  
Peter Warn ◽  
Christopher M Yates ◽  
Robert J Schotzinger
Keyword(s):  
Antifungal Activity ◽  
Invasive Aspergillosis ◽  
Murine Model ◽  
Pathogenic Fungi ◽  
Rational Drug Design ◽  
Fungal Burden ◽  
Delayed Treatment ◽  
Rational Drug

Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.

Enzyme regulation by biological disulfides

1989 ◽  
Vol 9 (5) ◽  
pp. 593-604 ◽  
Author(s):  
Raul N. Ondarza
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Regulatory Mechanism ◽  
Enzyme Regulation ◽  
Rational Drug Design ◽  
Host Cells ◽  
Disulfide Exchange ◽  
Rational Drug

More than a dozen enzymes have been found to be activated or inhibited in vitro by disulfide-exchange between the protein and small-molecule disulfides. Accordingly, thiol/disulfide ratio changes in vivo may be of great importance in the regulation of cellular metabolism. An awareness of this regulatory mechanism in both host cells and parasites, coupled with information on the presence or absence of key enzymes, may lead to rational drug design against certain diseases involving thiol intermediates, including trypanosomiasis.

Rational Drug Design

2014 ◽  
Vol 4 (1) ◽  
pp. 59-85 ◽  
Author(s):  
Khaled H. Barakat ◽  
Michael Houghton ◽  
D. Lorne Tyrrel ◽  
Jack A. Tuszynski
Keyword(s):  
Drug Design ◽  
Rational Drug Design ◽  
Dimensional Structure ◽  
Computational Tools ◽  
Structure Based Drug Design ◽  
Practical Applications ◽  
3 Dimensional ◽  
Drug Candidates ◽  
The Past ◽  
Rational Drug

For the past three decades rationale drug design (RDD) has been developing as an innovative, rapid and successful way to discover new drug candidates. Many strategies have been followed and several targets with diverse structures and different biological roles have been investigated. Despite the variety of computational tools available, one can broadly divide them into two major classes that can be adopted either separately or in combination. The first class involves structure-based drug design, when the target's 3-dimensional structure is available or it can be computationally generated using homology modeling. On the other hand, when only a set of active molecules is available, and the structure of the target is unknown, ligand-based drug design tools are usually used. This review describes some recent advances in rational drug design, summarizes a number of their practical applications, and discusses both the advantages and shortcomings of the various techniques used.

scholarly journals Fi-score: a novel approach to characterise protein topology and aid in drug discovery studies

2020 ◽  
Author(s):  
Austė Kanapeckaitė ◽  
Claudia Beaurivage ◽  
Matthew Hancock ◽  
Erik Verschueren
Keyword(s):  
Dihedral Angle ◽  
Target Selection ◽  
Gaussian Mixture Models ◽  
Drug Repurposing ◽  
Gaussian Mixture ◽  
Rational Drug Design ◽  
Drug Candidates ◽  
Novel Approach ◽  
Protein Fingerprinting ◽  
Rational Drug

AbstractTarget evaluation is at the centre of rational drug design and biologics development. In order to successfully engineer antibodies, T-cell receptors or small molecules it is necessary to identify and characterise potential binding or contact sites on therapeutically relevant target proteins. Currently, there are numerous challenges in achieving a better docking precision as well as characterising relevant sites. We devised a first-of-its-kind in silico protein fingerprinting approach based on dihedral angle and B-factor distribution to probe binding sites and sites of structural importance. In addition, we showed that the entire protein regions or individual structural subsets can be profiled using our derived fi-score based on amino acid dihedral angle and B-factor distribution. We further described a method to assess the structural profile and extract information on sites of importance using machine learning Gaussian mixture models. In combination, these biophysical analytical methods could potentially help to classify and systematically analyse not only targets but also drug candidates that bind to specific sites which would greatly improve pre-screening stage, target selection and drug repurposing efforts in finding other matching targets.

scholarly journals Rational Drug Design Rational Drug Design

2017 ◽  
pp. 1144-1174
Author(s):  
Khaled H. Barakat ◽  
Michael Houghton ◽  
D. Lorne Tyrrel ◽  
Jack A. Tuszynski
Keyword(s):  
Drug Design ◽  
Rational Drug Design ◽  
The Other ◽  
Dimensional Structure ◽  
Design Tools ◽  
Structure Based Drug Design ◽  
Practical Applications ◽  
3 Dimensional ◽  
Drug Candidates ◽  
Rational Drug

For the past three decades rationale drug design (RDD) has been developing as an innovative, rapid and successful way to discover new drug candidates. Many strategies have been followed and several targets with diverse structures and different biological roles have been investigated. Despite the variety of computational tools available, one can broadly divide them into two major classes that can be adopted either separately or in combination. The first class involves structure-based drug design, when the target's 3-dimensional structure is available or it can be computationally generated using homology modeling. On the other hand, when only a set of active molecules is available, and the structure of the target is unknown, ligand-based drug design tools are usually used. This review describes some recent advances in rational drug design, summarizes a number of their practical applications, and discusses both the advantages and shortcomings of the various techniques used.

scholarly journals In Silico Designing of Novel Thiazolidine-2-one Derivatives as Dual PDE4/7 Inhibitors for Inflammatory Disorders

2019 ◽  
Vol 5 (2) ◽  
pp. 149-162
Author(s):  
Ajmer Singh Grewal ◽  
Neelam Sharma ◽  
Sukhbir Singh ◽  
Sandeep Arora
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Docking Study ◽  
Rational Drug Design ◽  
Amino Acid Residues ◽  
Drug Candidates ◽  
Secondary Messenger ◽  
Inflammatory Conditions ◽  
Rational Drug ◽  
Dual Inhibitors

Phosphodiesterase 4 (PDE4) and phosphodiesterase 7 (PDE7), members of PDE super family, catalyse metabolism of secondary messenger cyclic adenosine monophosphate leading to augmented inflammatory processes in pro-inflammatory and immune-modulatory cells. Dual inhibitors of PDE4/7 are a novel class of drug candidates which can regulate pro-inflammatory as well as function of immune T-cell and are particularly beneficial for the treatment of various inflammatory diseasesdevoid of unwanted actions. Intense efforts have been directed towards the development of effective dual inhibitors of both PDE4 and PDE7, but not much success has been reported till yet. The aim of present study was to design some newer substituted thiazolidine-2-one derivatives as dual inhibitors of PDE4/7 using structure based rational drug design approach. A new series of thiazolidine-2-one analogues were designed and molecular docking was performed using AutoDock Vina to explore the bondinginteractions of the designed molecules with the amino acid residues in the active site of target proteins. The docking study indicated that all the substituted thiazolidine-2-one derivatives have appreciable binding interactions with protein residues of both PDE4 and PDE7. The newly designed compounds could be used as lead molecules for development potent and non-toxic dual inhibitors of PDE4/7 for the management of various inflammatory conditions.

From serendipity to rational drug design in brain disorders: in silico, in vitro, and in vivo approaches

2021 ◽  
Vol 60 ◽  
pp. 177-182
Author(s):  
Hyunjung Oh ◽  
Thomas D. Prevot ◽  
Dwight Newton ◽  
Etienne Sibille
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Rational Drug Design ◽  
Brain Disorders ◽  
Rational Drug

scholarly journals Rational Drug Design of Targeted and Enzyme Cleavable Vitamin E Analogs as Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of Cardiotoxicity of Doxorubicin.

2021 ◽  
Author(s):  
Raghu S Pandurangi ◽  
Orsolya Cseh ◽  
Artee Luchman ◽  
siguang Xu ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Vitamin E ◽  
Drug Design ◽  
Cancer Cells ◽  
Water Solubility ◽  
Therapeutic Index ◽  
Rational Drug Design ◽  
In Vivo Evaluation ◽  
Rational Drug

Traditional drug design focus on specific target (s) expressed by cancer cells. However, cancer cells outsmart the interventions by activating survival pathways and/or downregulating cell death pathways. As the research in molecular biology of cancer grows exponentially, new methods of drug designs are needed to target multiple pathways/targets which are involved in survival of cancer cells. Vitamin E analogues including a-tocopheryl succinate (TOS) is a well-known anti-tumoregenic agent which is well studied both in vitro and in vivo tumor models. However, lack of targeting cancer cells and unexpected toxicity along with the poor water solubility of TOS compelled a rational drug design using both targeting and cleavable technologies incorporated in the new drug design. A plethora of Vitamin E derivatives (AMP-001, 002 and 003) were synthesized, characterized and studied for the improved efficacy and lowered toxicity in various cancer cells in vitro. Preliminary studies revealed AAAPT leading candidates reduced the invasive potential of brain tumor stem cells, synergized with different drugs and different treatments. AAAPT leading drug AMP-001 enhanced the therapeutic index of front-line drug Doxorubicin in triple negative breast cancer (TNBC) tumor rat model preserving the ventricular function when used as a neoadjuvant to Doxorubicin. These results may pave the way for reducing the cardiotoxicity of chemotherapy in clinical settings.

scholarly journals Egr-1 abrogates the block imparted by c-Myc on terminal M1 myeloid differentiation

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 871-878 ◽  
Author(s):  
Marianna Shafarenko ◽  
Dan A. Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Suppressor Gene ◽  
Rational Drug Design ◽  
Monocytic Differentiation ◽  
Altered Expression ◽  
Rational Drug ◽  
Cell Growth And Differentiation ◽  
Differentiation Inducer

AbstractBoth deregulated growth and blocks in differentiation cooperate in the multistage process of leukemogenesis. Thus, understanding functional interactions between genes that regulate normal blood cell development, including cell growth and differentiation, and how their altered expression contributes to leukemia, is important for rational drug design. Previously, we have shown that the zinc finger transcription factor Egr-1 plays a role in monocytic differentiation. Ectopic expression of Egr-1 in M1 myeloblastic leukemia cells was observed to activate the macrophage differentiation program in the absence of the differentiation inducer interleukin 6 (IL-6) and to promote terminal differentiation in its presence. In addition, we have shown that deregulated expression of the proto-oncogene c-myc blocks the myeloid terminal differentiation program. Here we show that restoring expression of Egr-1 in M1 cells that express deregulated c-Myc abrogates the c-Myc block in terminal differentiation, resulting in cells that undergo functional macrophage maturation. However, there is an absence of both growth arrest and cell adhesion. In addition, Egr-1 expression diminished M1myc leukemogenicity in vivo. These findings indicate that Egr-1 can act as a tumor suppressor gene and suggest that Egr-1 or Egr-1 targets may provide important tools for differentiation therapy in certain leukemic phenotypes.

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