Drug design

Summary

Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially ther

Official source

https://en.wikipedia.org/wiki/Drug_design

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On the role of water density fluctuations in the inhibition of a proton channel

Lucie Monique Françoise Delemotte

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.

Natl Acad Sciences2016

Repurposed drug combination via high-throughput screening and dual drug delivery system development for the treatment of retinoblastoma

Po-Jen Tseng

The goal of retinoblastoma (RB) treatment is to save the child's life, eyes and functional vision, with that order of priority. The management of RB is complex and involves strategically chosen methods of surgical enucleation, external beam radiotherapy, intravenous chemoreduction and focal therapy. Local administration routes of chemotherapy, intra-arterial (IAC) and intravitreal (IVC), have emerged as promising methods to salvage the eyes and vision. New improvements in the chemotherapy of RB are geared towards reducing side effects of the drugs employed. Emerging strategies includes alternative chemotherapeutic agents, drug combinations, and novel drug delivery systems. Most successful examples of drug repurposing so far have been serendipitous. The systematic approach here was identified candidate drugs by strategic high-throughput screening methods. In this thesis, hit drugs were screened from a drug library of primarily FDA-approved drugs, and the synergistic effect of selected drug combinations was investigated. The hit drug gemcitabine, known to be an effective clinical treatment for non-small cell lung cancers, in combination with carboplatin, was discovered to have the highest cytotoxicity of the hits identified, and appeared as a potential alternative therapeutic agent for RB treatment.Polymeric nanoparticles (NPs) as an improved drug delivery system were investigated with gemcitabine. The nanoprecipitation synthesis of a poly(lactic-co-glycolic acid), as known as PLGA, nanoparticle was developed for drug encapsulation. The characterization of PLGA NPs within various active pharmaceutical ingredients were studied using dynamic light scattering and scanning electron microscopy, revealing that spherical NPs ranging in size from 150 to 200 nm could be successfully prepared. The tumor cells proliferation inhibition was observed after treatment with this novel nanoformulation. Furthermore, the possibility of a dual drug delivery system was explored. Gemcitabine and carboplatin were encapsulated together in PLGA NPs and found to show a synergistic effect after dual drug release. Additionally, gemcitabine combined with the light-activated agent indocyanine green was prepared, and laser-induced photothermal therapy (PTT) was explored.

EPFL2022

It is now clear that some cysteines on some proteins are highly tuned to react with electrophiles. Based on numerous studies, it is also established that electrophile sensing underpins rewiring of several critical signaling processes. These electrophile-sensing proteins, or privileged first responders (PFRs), are likely critically relevant for drug design. However, identifying PFRs remains a challenging and unsolved problem, despite the development of several high-throughput methods to ID proteins that react with electrophiles. More importantly, we remain unable to rank how different PFRs identified under different conditions relate to one another, in terms of sensing or signaling capacity. Here we evaluate different methods to assay sensing functions of proteins and discuss these methods in the context of developing a "ranking scheme." Based on theoretical and experimental evidence, we propose that T-REX-the only targeted-electrophile delivery tool presently available-is a reliable method to rank PFRs. Finally, we address to what extent electrophile sensing and downstream signaling are correlated. Based on our current data, we observe that such behaviors are indeed correlated. It is our hope that through this manuscript researchers from various arms of the stress signaling fields will focus on developing a quantitative understanding of precision electrophile labeling.

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD2020

Repurposed drug combination via high-throughput screening and dual drug delivery system development for the treatment of retinoblastoma

Po-Jen Tseng

EPFL2022