Drug Discovery and Molecular Dynamics: Methods, Applications and Perspective Beyond the Second Timescale

Martínez-Rosell, Gerard; Giorgino, Toni; Harvey, Matt; Fabritiis, Gianni De

doi:10.2174/1568026617666170414142549

Cited by 36 publications

(33 citation statements)

References 79 publications

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“…The combination of these two methods seems to be crucial in order to improve predictions accuracy and speed up the MD analysis process. ML/MD combined approach, together with a continuous increasing simulation timescale, as observed by Martinéz-Rossell et al 157 in their recent overview, depict without any doubt an encouraging landscape for researchers, paving the way for "drugging the undruggable targets".…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 94%

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

et al. 2018

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Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 94%

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

et al. 2018

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“…There are important software and hardware innovations including the specialized supercomputers such as ANTON and the implementation of MD codes on GPUs . It had been estimated that MD would reach aggregated sampling of second timescale by around 2022 . Here, we propose that MD simulations would play an important role in the functional design of aptamers as well as aptamer–target interaction studies for enhanced biomarking.…”

Section: Introductionmentioning

confidence: 99%

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Jeevanandam

Tan

Danquah

et al. 2020

Biotechnology Journal

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Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non‐targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer–target binding results from several inter‐molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer‐mediated receptor targeting in targeted cancer therapy. MD simulation offers real‐time analysis of the molecular drivers of the aptamer‐receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.

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“…Though initial applications of GPUs were exclusively for creation of computer graphics, GPUs have matured to a state where they can be applied for non-graphical purposes. The newer general purpose graphics processing units (GPGPUs) have received considerable attention in computational chemistry, notably as molecular dynamics simulations have exploited the vector and matrix processing capabilities of GPGPUs to improve the time to compute the per-frame trajectories of individual atoms in a system by orders of magnitude [1,2]. Another pharmaceutically relevant application of GPU technology has been to construct systems for analysis of high-content imaging systems, notably phenotypic cellular response to chemical perturbation.…”

Section: Introductionmentioning

confidence: 99%

Advancing drug discovery via GPU-based deep learning

Gawehn

Hiss

Brown

et al. 2018

Expert Opinion on Drug Discovery

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Drug Discovery and Molecular Dynamics: Methods, Applications and Perspective Beyond the Second Timescale

Cited by 36 publications

References 79 publications

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Advancing drug discovery via GPU-based deep learning

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