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Published year: 20239
An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration

Abstract (Expand)

Abstract Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid …thesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δ etr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.

Authors: M. Tanvir Rahman, M. Kristian Koski, Joanna Panecka-Hofman, Werner Schmitz, Alexander J. Kastaniotis, Rebecca C. Wade, Rik K. Wierenga, J. Kalervo Hiltunen, Kaija J. Autio

Date Published: 1st Dec 2023

Publication Type: Journal

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance

Abstract (Expand)

Abstract The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to …r systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. Here, we describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and a polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA) or hydroxypropyl methylcellulose acetate succinate, with or without Na + /K + salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of a low-dosage regimen for this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.

Authors: Sumit Mukesh, Goutam Mukherjee, Ridhima Singh, Nathan Steenbuck, Carolina Demidova, Prachi Joshi, Abhay T. Sangamwar, Rebecca C. Wade

Date Published: 1st Dec 2023

Publication Type: Journal

Wird KI neue Medikamente gegen Herzkrankheiten hervorbringen?

Abstract (Expand)

Zusammenfassung Angesichts der umwälzenden Auswirkungen, die künstliche Intelligenz (KI) auf Wissenschaft, Medizin und darüber hinaus hat, betrachten wir hier das Potenzial von KI für die Entdeckung …enzial von KI für die Entdeckung neuer Medikamente gegen Herzkrankheiten. Wir definieren KI im weitesten Sinne als den Einsatz von maschinellem Lernen, einschließlich Statistik und Deep Learning, um Muster in Datensätzen zu erkennen, die für Vorhersagen genutzt werden können. Jüngste Durchbrüche in der Fähigkeit, sehr große Datenmengen zu berücksichtigen, haben einen Boom in der KI-gestützten Arzneimittelentdeckung sowohl in der Wissenschaft als auch in der Industrie ausgelöst. Viele neue Unternehmen verfügen bereits über Arzneimittel-Pipelines, die bis in die klinische Erprobung reichen, aber noch keine Medikamente gegen Herzkrankheiten enthalten. Wir beschreiben hier den Einsatz von KI für die Entdeckung von niedermolekularen Medikamenten und Biologika, einschließlich therapeutischer Peptide, sowie für die Vorhersage von Wirkungen wie Kardiotoxizität. Der konzertierte Einsatz von KI zusammen mit physikbasierten Simulationen und experimentellen Rückkopplungsschleifen wird notwendig sein, um das Potenzial der KI für die Arzneimittelentdeckung und die Entwicklung von Präzisionsarzneimitteln für Herzkrankheiten voll auszuschöpfen.

Authors: Manuel Glaser, Julia Ritterhof, Patrick Most, Rebecca C. Wade

Date Published: 20th Nov 2023

Publication Type: Journal

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Abstract

Not specified

Authors: Marina Roussaki, George E. Magoulas, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Ina Pöhner, Sara Luelmo, Pantelis Afroudakis, Kalliopi Georgikopoulou, Paloma Tejera Nevado, Julia Eick, Eugenia Bifeld, María J. Corral, María Dolores Jiménez-Antón, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Sheraz Gul, Joachim Clos, Kyriakos C. Prousis, Juan J. Torrado, José María Alunda, Rebecca C. Wade, Wanderley de Souza, Anabela Cordeiro da Silva, Theodora Calogeropoulou

Date Published: 1st Sep 2023

Publication Type: Journal

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Abstract

Not specified

Authors: Lucas G. Viviani, Daria B. Kokh, Rebecca C. Wade, Antonia T.-do Amaral

Date Published: 14th Aug 2023

Publication Type: Journal

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

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