New perspectives in cancer drug development: computational advances with an eye to design

Castelli, Matteo; Serapian, Stefano A.; Marchetti, Filippo; Triveri, Alice; Pirota, Valentina; Torielli, Luca; Collina, Simona; Doria, Filippo; Freccero, Mauro; Colombo, Giorgio

doi:10.1039/d1md00192b

Cited by 9 publications

(5 citation statements)

References 92 publications

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“…Belonging to the family of hexacyclic quinazolinone alkaloids, bioactive chaetominines have received much attention among chemists and biochemists. 11 On the basis of 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics simulations, 12 we designed chaetominine mimics in continuous pursuit of ASK1 and PI3K inhibitors. 13 Based on the structure virtual screening, the l -phenylalanine derivative 19 was chosen as a promising intermediate through rational dockings, in addition to the comparison with the PI3K pan-inhibitor copanlisib.…”

Section: Resultsmentioning

confidence: 99%

The quantitative pyrrole protection of l-phenylalanine/l-phenylalaninol in aqueous media and rationally updating the mechanisms of the Clauson-Kaas reaction through DFT study

Qin,

Cao,

Parmar

et al. 2023

RSC Adv.

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Section: Resultsmentioning

confidence: 99%

The quantitative pyrrole protection of l-phenylalanine/l-phenylalaninol in aqueous media and rationally updating the mechanisms of the Clauson-Kaas reaction through DFT study

Qin,

Cao,

Parmar

et al. 2023

RSC Adv.

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“…To the best of our knowledge, unbiased classical MD simulations aiming at describing the process by which the drug–target binding occurs are only few [ 40 , 41 , 42 , 43 ]. Most of the studies often focus on a ligand that already interacts or is near the binding site, using molecular docking or manual addition of the drug on the binding pocket to generate the pose used as a starting point.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

Vigna

Scoditti

Spinello³

et al. 2022

IJMS

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Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation.

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“…On the contrary, with the advent of CPU, GPU resources, and improved force fields, computational methods have shown dramatic improvement in determining the binding affinity between biomolecules [ 7 , 8 ]. Methods such as molecular docking, molecular dynamics, MM-PBSA binding free energy, umbrella sampling, free energy perturbation (FEP), and thermodynamic integration (TI) have been developed and effectively used for binding affinity assessment in kinase drug design [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

Ghosh

Cho

2023

Molecules

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Precise binding affinity predictions are essential for structure-based drug discovery (SBDD). Focal adhesion kinase (FAK) is a member of the tyrosine kinase protein family and is overexpressed in a variety of human malignancies. Inhibition of FAK using small molecules is a promising therapeutic option for several types of cancer. Here, we conducted computational modeling of FAK-targeting inhibitors using three-dimensional structure–activity relationship (3D-QSAR), molecular dynamics (MD), and hybrid topology-based free energy perturbation (FEP) methods. The structure–activity relationship (SAR) studies between the physicochemical descriptors and inhibitory activities of the chemical compounds were performed with reasonable statistical accuracy using CoMFA and CoMSIA. These are two well-known 3D-QSAR methods based on the principle of supervised machine learning (ML). Essential information regarding residue-specific binding interactions was determined using MD and MM-PB/GBSA methods. Finally, physics-based relative binding free energy (∆∆GRBFEA→B) terms of analogous ligands were estimated using alchemical FEP simulation. An acceptable agreement was observed between the experimental and computed relative binding free energies. Overall, the results suggested that using ML and physics-based hybrid approaches could be useful in synergy for the rational optimization of accessible lead compounds with similar scaffolds targeting the FAK receptor.

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New perspectives in cancer drug development: computational advances with an eye to design

Abstract: Computational chemistry has come of age in drug discovery. Indeed, most pharmaceutical development programs rely on computer-based data and results at some point. Herein, we discuss recent applications of advanced...

Cited by 9 publications

References 92 publications

The quantitative pyrrole protection of l-phenylalanine/l-phenylalaninol in aqueous media and rationally updating the mechanisms of the Clauson-Kaas reaction through DFT study

The quantitative pyrrole protection of l-phenylalanine/l-phenylalaninol in aqueous media and rationally updating the mechanisms of the Clauson-Kaas reaction through DFT study

Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

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