International Journal of Molecular Sciences

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Dr. Ηaralampos Tzoupis

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Department of Chemistry, University of Patras, 26504 Rion, Greece
Interests: computational biology; GPCRs; T-cell receptors; structure-based drug design; biochemistry; peptide conjugates; protein-ligand interactions; molecular dynamics protein simulations; design of non-peptide/peptide mimetics

Special Issue Information

Dear Colleagues,

Drug design comprises an important aspect of our understanding of biochemical pathways inside the cell, since it offers valuable information with regard to the role of various proteins. The process involves numerous steps, from identifying a suitable drug target to the evaluation of the various properties (physicochemical and ADMET) of the designed molecule. In order to facilitate the drug development process, various computational techniques have been and are being developed. These in silico tools address various issues, such as binding affinity predictions and interactions (e.g., molecular docking, molecular dynamics) and the prediction of ADMET properties. Additionally, various curated databases offer an extensive trove of data (experimental and predicted) that can be exploited in order to further empower the predictive strength of available and novel techniques. Moreover, the advent of AI and neural networks offers a powerful tool that can be exploited in order to address the vast quantity of accumulated data and assist in medicinal chemistry.

The aim of this Special Issue is to address the prospects offered by computational tools in the development of new molecules and the impact of innovative techniques on medicinal chemistry via the publication of communications, reviews and full papers focused on the above aspects.

Dr. Ηaralampos Tzoupis
Guest Editor

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Keywords

drug design
protein–ligand interactions
drug delivery systems
binding affinity prediction
drug repurposing
multidisciplinary approaches
toxicity prediction
machine learning drug design

Published Papers (2 papers)

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Research

21 pages, 5874 KiB

Open AccessArticle

Inhibitor Trapping in Kinases

by Danislav S. Spassov, Mariyana Atanasova and Irini Doytchinova

Int. J. Mol. Sci. 2024, 25(6), 3249; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063249 - 13 Mar 2024

Viewed by 573

Abstract

Recently, we identified a novel mechanism of enzyme inhibition in N-myristoyltransferases (NMTs), which we have named ‘inhibitor trapping’. Inhibitor trapping occurs when the protein captures the small molecule within its structural confines, thereby preventing its free dissociation and resulting in a dramatic increase in inhibitor affinity and potency. Here, we demonstrate that inhibitor trapping also occurs in the kinases. Remarkably, the drug imatinib, which has revolutionized targeted cancer therapy, is entrapped in the structure of the Abl kinase. This effect is also observed in p38α kinase, where inhibitor trapping was found to depend on a ‘magic’ methyl group, which stabilizes the protein conformation and increases the affinity of the compound dramatically. Altogether, these results suggest that inhibitor trapping is not exclusive to N-myristoyltransferases, as it also occurs in the kinase family. Inhibitor trapping could enhance the binding affinity of an inhibitor by thousands of times and is as a key mechanism that plays a critical role in determining drug affinity and potency. Full article

(This article belongs to the Special Issue Computational Medicine and Molecular Drug Design)

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17 pages, 2610 KiB

Open AccessArticle

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations

by Paulina Valenzuela-Hormazabal, Romina V. Sepúlveda, Melissa Alegría-Arcos, Elizabeth Valdés-Muñoz, Víctor Rojas-Pérez, Ileana González-Bonet, Reynier Suardíaz, Christian Galarza, Natalia Morales, Verónica Leddermann, Ricardo I. Castro, Bruna Benso, Gabriela Urra, Erix W. Hernández-Rodríguez and Daniel Bustos

Int. J. Mol. Sci. 2024, 25(4), 1968; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25041968 - 06 Feb 2024

Cited by 1 | Viewed by 945

Abstract

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea. Full article

(This article belongs to the Special Issue Computational Medicine and Molecular Drug Design)

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