Filter and export

Publications

What is a Publication?
357 Publications visible to you, out of a total of 357
PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport

Abstract (Expand)

The chloroquine resistance transporter (PfCRT) confers resistance to a wide range of quinoline and quinoline-like antimalarial drugs in Plasmodium falciparum , with local drug histories driving its …rum , with local drug histories driving its evolution and, hence, the drug transport specificities. For example, the change in prescription practice from chloroquine (CQ) to piperaquine (PPQ) in Southeast Asia has resulted in PfCRT variants that carry an additional mutation, leading to PPQ resistance and, concomitantly, to CQ re-sensitization. How this additional amino acid substitution guides such opposing changes in drug susceptibility is largely unclear. Here, we show by detailed kinetic analyses that both the CQ- and the PPQ-resistance conferring PfCRT variants can bind and transport both drugs. Surprisingly, the kinetic profiles revealed subtle yet significant differences, defining a threshold for in vivo CQ and PPQ resistance. Competition kinetics, together with docking and molecular dynamics simulations, show that the PfCRT variant from the Southeast Asian P . falciparum strain Dd2 can accept simultaneously both CQ and PPQ at distinct but allosterically interacting sites. Furthermore, combining existing mutations associated with PPQ resistance created a PfCRT isoform with unprecedented non-Michaelis-Menten kinetics and superior transport efficiency for both CQ and PPQ. Our study provides additional insights into the organization of the substrate binding cavity of PfCRT and, in addition, reveals perspectives for PfCRT variants with equal transport efficiencies for both PPQ and CQ.

Authors: Guillermo M. Gomez, Giulia D’Arrigo, Cecilia P. Sanchez, Fiona Berger, Rebecca C. Wade, Michael Lanzer

Date Published: 7th Jun 2023

Publication Type: Journal

Brownian dynamics simulations of biomolecular diffusional association processes

Abstract (Expand)

Abstract Brownian dynamics (BD) is a computational method to simulate molecular diffusion processes. Although the BD method has been developed over several decades and is well established, new …d is well established, new methodological developments are improving its accuracy, widening its scope, and increasing its application. In biological applications, BD is used to investigate the diffusive behavior of molecules subject to forces due to intermolecular interactions or interactions with material surfaces. BD can be used to compute rate constants for diffusional association, generate structures of encounter complexes for molecular binding partners, and examine the transport properties of geometrically complex molecules. Often, a series of simulations is performed, for example, for different protein mutants or environmental conditions, so that the effects of the changes on diffusional properties can be estimated. While biomolecules are commonly described at atomic resolution and internal molecular motions are typically neglected, coarse‐graining and the treatment of conformational flexibility are increasingly employed. Software packages for BD simulations of biomolecules are growing in capabilities, with several new packages providing novel features that expand the range of questions that can be addressed. These advances, when used in concert with experiment or other simulation methods, such as molecular dynamics, open new opportunities for application to biochemical and biological systems. Here, we review some of the latest developments in the theory, methods, software, and applications of BD simulations to study biomolecular diffusional association processes and provide a perspective on their future use and application to outstanding challenges in biology, bioengineering, and biomedicine. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Software > Simulation Methods

Authors: Abraham Muñiz‐Chicharro, Lane W. Votapka, Rommie E. Amaro, Rebecca C. Wade

Date Published: 1st May 2023

Publication Type: Journal

Scaling Protein–Water Interactions in the Martini 3 Coarse-Grained Force Field to Simulate Transmembrane Helix Dimers in Different Lipid Environments

Abstract

Not specified

Authors: Ainara Claveras Cabezudo, Christina Athanasiou, Alexandros Tsengenes, Rebecca C. Wade

Date Published: 11th Apr 2023

Publication Type: Journal

Multiscale molecular simulations to investigate adenylyl cyclase‐based signaling in the brain

Abstract (Expand)

Abstract Adenylyl cyclases (ACs) play a key role in many signaling cascades. ACs catalyze the production of cyclic AMP from ATP and this function is stimulated or inhibited by the binding of their …ed by the binding of their cognate stimulatory or inhibitory Gα subunits, respectively. Here we used simulation tools to uncover the molecular and subcellular mechanisms of AC function, with a focus on the AC5 isoform, extensively studied experimentally. First, quantum mechanical/molecular mechanical free energy simulations were used to investigate the enzymatic reaction and its changes upon point mutations. Next, molecular dynamics simulations were employed to assess the catalytic state in the presence or absence of Gα subunits. This led to the identification of an inactive state of the enzyme that is present whenever an inhibitory Gα is associated, independent of the presence of a stimulatory Gα. In addition, the use of coevolution‐guided multiscale simulations revealed that the binding of Gα subunits reshapes the free‐energy landscape of the AC5 enzyme by following the classical population‐shift paradigm. Finally, Brownian dynamics simulations provided forward rate constants for the binding of Gα subunits to AC5, consistent with the ability of the protein to perform coincidence detection effectively. Our calculations also pointed to strong similarities between AC5 and other AC isoforms, including AC1 and AC6. Findings from the molecular simulations were used along with experimental data as constraints for systems biology modeling of a specific AC5‐triggered neuronal cascade to investigate how the dynamics of downstream signaling depend on initial receptor activation. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Software > Molecular Modeling

Authors: Siri C. van Keulen, Juliette Martin, Francesco Colizzi, Elisa Frezza, Daniel Trpevski, Nuria Cirauqui Diaz, Pietro Vidossich, Ursula Rothlisberger, Jeanette Hellgren Kotaleski, Rebecca C. Wade, Paolo Carloni

Date Published: 2023

Publication Type: Journal

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth.

Abstract (Expand)

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression … of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.

Authors: L. Costantino, S. Ferrari, M. Santucci, O. M. H. Salo-Ahen, E. Carosati, S. Franchini, A. Lauriola, C. Pozzi, M. Trande, G. Gozzi, P. Saxena, G. Cannazza, L. Losi, D. Cardinale, A. Venturelli, A. Quotadamo, P. Linciano, L. Tagliazucchi, M. G. Moschella, R. Guerrini, S. Pacifico, R. Luciani, F. Genovese, S. Henrich, S. Alboni, N. Santarem, A. da Silva Cordeiro, E. Giovannetti, G. J. Peters, P. Pinton, A. Rimessi, G. Cruciani, R. M. Stroud, R. C. Wade, S. Mangani, G. Marverti, D. D'Arca, G. Ponterini, M. P. Costi

Date Published: 7th Dec 2022

Publication Type: Journal

Identification of antiparasitic drug targets using a multi-omics workflow in the acanthocephalan model

Abstract (Expand)

Abstract Background With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated …er, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans ( Pomphorhynchus laevis, Neoechinorhynchus agilis , Neoechinorhynchus buttnerae ) from four fish species (common barbel, European eel, thinlip mullet, tambaqui). Results The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel. Conclusions The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URL tinyurl.com/yx72rda7 .

Authors: Hanno Schmidt, Katharina Mauer, Manuel Glaser, Bahram Sayyaf Dezfuli, Sören Lukas Hellmann, Ana Lúcia Silva Gomes, Falk Butter, Rebecca C. Wade, Thomas Hankeln, Holger Herlyn

Date Published: 1st Dec 2022

Publication Type: Journal

MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I

Abstract

Not specified

Authors: Marcus Fabiano de Almeida Mendes, Marcelo de Souza Bragatte, Priscila Vianna, Martiela Vaz de Freitas, Ina Pöhner, Stefan Richter, Rebecca C. Wade, Francisco Mauro Salzano, Gustavo Fioravanti Vieira

Date Published: 28th Oct 2022

Publication Type: Journal

Powered by
 (v.1.16.0)
About HITS Publication SEEK | About HITS-Publication-SEEK | Funding and Programmes | Credits
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH