Searching for protein binding sites from Molecular Dynamics simulations and paramagnetic fragment-based NMR studies

Bernini, Andrea; Angelis, Lucia Henrici De; Morandi, Edoardo; Spiga, Ottavia; Santucci, Annalisa; Assfalg, Michael; Molinari, Henríette; Pillozzi, Serena; Arcangeli, Annarosa; Niccolai, Neri

doi:10.1016/j.bbapap.2013.12.012

Cited by 18 publications

(14 citation statements)

References 33 publications

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“…The CXCR4 [18][19][20][21][22][23][24][25][26][27] sequence, on the contrary, exhibited no binding to CXCL12 when used as a fragment. Due to the lack of binding data for the remaining sequence CXCR4 [28][29][30][31][32][33][34][35][36][37][38] and the large conformational variability in the CXCL12/CXCR4 1-38 structure, the peptide spanning aa 29-35 (termed 4-29-35) of CXCR4 was selected for the evaluation of binding capability of this region.…”

Section: Resultsmentioning

confidence: 94%

“…Small molecules modulating the CXCR4/CXCL12 interaction were selected from a virtual library [Clean Leads subset from ZINC database; (30)] using experimental data as constraints for a molecular docking simulation. In particular, all molecules were docked to the transient binding pocket opening on Val23/Ala40 (22). Transient pockets, indeed, refer to their rapid appearance and disappearance on flat protein surfaces as a consequence of fluctuations in conformational dynamics [hence the definition of dynamic drug design (DDD)].…”

Section: Resultsmentioning

confidence: 99%

“…Transient pockets, indeed, refer to their rapid appearance and disappearance on flat protein surfaces as a consequence of fluctuations in conformational dynamics [hence the definition of dynamic drug design (DDD)]. The presence of such a pocket was inferred by an NMR paramagnetic perturbation study, while the open conformation was determined by trajectory analysis of molecular dynamics simulation of CXCL12 (22). The trajectory frame representing the pocket open conformation was used for the docking run, and the simulation box was narrowed down to the involved residues V23, K24, H25, K27, A40, R41 and K43.…”

Section: Resultsmentioning

confidence: 99%

“…Small molecules were injected over a CXCL12-coated chip for 60 sec at a flow rate of 30 µl/min and diluted at 100 µM in 5% dimethyl sulfoxide-HBS-EP + , which was also used as the running buffer. Molecular docking simulation was performed using the AutoDock Vina package v 1.1.2 (23) using a ZINC-derived library (http://zinc.docking.org) of small molecules probed against a CXCL12 pocket region previously identified by NMR experiments and MD simulations (22), and consisting of residues V23, K24, H25, K27, A40, R41 and K43. Standard Vina parameters were used for the simulation runs.…”

Section: Methodsmentioning

confidence: 99%

“…Novel tools targeting CXCL12 have recently been developed by means of combining paramagnetic fragment-based nuclear magnetic resonance (NMR) investigation, molecular dynamics (MD) and docking simulations (22). We here provide in vitro biological data on the effects of some of these molecules on acute leukemia cell survival.…”

Section: Introductionmentioning

confidence: 99%

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Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

et al. 2018

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Notable advances in treatment have been made and increases in the cure rates of pediatric leukemia have been achieved. However, the majority of children with relapsed disease are not expected to survive, with chemotherapy resistance acting as the principal cause of treatment failure. Interaction between leukemic cells and the bone marrow microenvironment is the primary cause of relapse. It was identified that a multi-protein membrane complex, formed by potassium voltage-gated channel subfamily H member 2 (hERG1) channels, the β1 integrin subunit and the stromal cell-derived factor 12 (CXCL12) receptor, C-X-C chemokine receptor type 4 (CXCR4), exerts a role in mesenchymal stromal cell (MSC)-mediated chemoresistance in pediatric leukemias. hERG1 blockade was able to overcome chemoresistance in vitro and in vivo. As an alternative strategy to overcome chemoresistance, the present study evaluated the effects of novel tools targeting the CXCR4/CXCL12 axis. The analysis of CXCL12 structural dynamics was used for the selection of a peptide (4-1-17) and a small molecule (8673), which interact with a transient hot spot, identified by a dynamic drug design approach. The present findings indicated that peptide 4-1-17 and small molecule 8673 inhibited leukemia cell proliferation and induced a pro-apoptotic effect, which was not reduced by the presence of MSCs. The combined treatment with 4-1-17 and 8673 had a stronger pro-apoptotic effect, particularly on cells cultured on MSCs in normoxic and hypoxic conditions, and was able to overcome MSC-induced resistance to cytarabine. Overall, the targeting of CXCL12 and the ensuing inhibition of the CXCR4/CXCL12 axis may be proposed as an alternative strategy to overcome chemoresistance in leukemia.type 4/stromal cell-derived factor 12 axis, dynamic drug design, protein-protein interaction disruptors, potassium voltage-gated channel subfamily H member 2 channels, bone marrow stromal cells

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

et al. 2018

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Tailoring Hit Identification and Qualification Methods for Targeting Protein–Protein Interactions

Walse

Turnbull²,

Boyd³

2017

Applied Biophysics for Drug Discovery

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Computational structure‐based drug design: Predicting target flexibility

Iglesias¹,

Saen‐oon²,

Soliva³

et al. 2018

WIREs Comput Mol Sci

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The role of molecular modeling in drug design has experienced a significant revamp in the last decade. The increase in computational resources and molecular models, along with software developments, is finally introducing a competitive advantage in early phases of drug discovery. Medium and small companies with strong focus on computational chemistry are being created, some of them having introduced important leads in drug design pipelines. An important source for this success is the extraordinary development of faster and more efficient techniques for describing flexibility in three‐dimensional structural molecular modeling. At different levels, from docking techniques to atomistic molecular dynamics, conformational sampling between receptor and drug results in improved predictions, such as screening enrichment, discovery of transient cavities, etc. In this review article we perform an extensive analysis of these modeling techniques, dividing them into high and low throughput, and emphasizing in their application to drug design studies. We finalize the review with a section describing our Monte Carlo method, PELE, recently highlighted as an outstanding advance in an international blind competition and industrial benchmarks. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Software > Molecular Modeling

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Searching for protein binding sites from Molecular Dynamics simulations and paramagnetic fragment-based NMR studies

Cited by 18 publications

References 33 publications

Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

Tailoring Hit Identification and Qualification Methods for Targeting Protein–Protein Interactions

Computational structure‐based drug design: Predicting target flexibility

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