International Journal of Molecular Sciences

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Dear Colleagues,

The integration of computers in the drug-discovery process is an established and essential aspect of modern drug development. The use of advanced computational techniques has significantly enhanced the efficiency and effectiveness of drug development by enabling the analysis of complex biological data, the simulations of drug interactions and the prediction of potential drug efficacy and mechanisms of action. In addition, the use of computer-aided drug design (CADD) methods has facilitated the discovery of new drug candidates by enabling the rational design of compounds with improved pharmacological properties, often considering the structural nature of the target and potential drug molecules. New revolutionizing tools continue to appear, such as AlphaFold and RosettaFold, opening new ways of addressing human health from a structural perspective.

This Special Issue will focus on the application of structural bioinformatics to human health, particularly through techniques that emphasize a molecular analysis of the problem. Examples include homology modelling, structure-based drug design and discovery, atomistic molecular dynamics simulations drug-target interactions and other in silico techniques that integrate the structural perspective of molecules and their potential targets in the drug-development process.

Dr. Sérgio F. Sousa
Guest Editor

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Keywords

homology modelling
SBVS
docking
CADD

Published Papers (1 paper)

Research

15 pages, 2315 KiB

Open AccessArticle

Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

by Maria Chiara Scaini, Luisa Piccin, Davide Bassani, Antonio Scapinello, Stefania Pellegrini, Cristina Poggiana, Cristina Catoni, Debora Tonello, Jacopo Pigozzo, Luigi Dall’Olmo, Antonio Rosato, Stefano Moro, Vanna Chiarion-Sileni and Chiara Menin

Int. J. Mol. Sci. 2023, 24(15), 12285; https://doi.org/10.3390/ijms241512285 - 31 Jul 2023

Cited by 2 | Viewed by 1728

Abstract

The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy. Full article

(This article belongs to the Special Issue Structural Bioinformatics: Molecular Regulation of Drug Design and Targeted Therapy in Human Health)

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Structural Bioinformatics: Molecular Regulation of Drug Design and Targeted Therapy in Human Health

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