Rapid decomposition and visualisation of protein–ligand binding free energies by residue and by water

Woods, Christopher; Malaisree, Maturos; Michel, Julien; Long, Ben; McIntosh–Smith, Simon; Mulholland, Adrian J.

doi:10.1039/c3fd00125c

Cited by 81 publications

(83 citation statements)

References 45 publications

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“…The crystallographic structure of human thrombin in a complex with a thrombin ligand structurally related to the ligands simulated in this study was downloaded from the PDB databank 19 (PDB code 2ZC9 17 ). The protein structure was inspected and prepared for molecular simulations using Maestro.…”

Section: Protein Structure Setupmentioning

confidence: 99%

“…The side chain of Arg75 in the heavy chain (chain H) of thrombin was partially resolved. 19 Missing atoms were added to complete the side-chain in a solvent exposed conformation. 19 The incomplete light chain was capped before Glu1C with an ACE residue and after Ile14L with an NME residue.…”

Section: Protein Structure Setupmentioning

confidence: 99%

“…19 Missing atoms were added to complete the side-chain in a solvent exposed conformation. 19 The incomplete light chain was capped before Glu1C with an ACE residue and after Ile14L with an NME residue. 19 The incomplete heavy chain was capped after Gly246 with an NME residue.…”

Section: Protein Structure Setupmentioning

confidence: 99%

“…19 The incomplete heavy chain was capped after Gly246 with an NME residue. 19 Missing residues Trp148, Thr149, Ala149A, Asn149B, Val149C, Gly149D, Lys149E in chain H were modeled in the structure using the FALC-Loop web server 21 . Standard protonation states were assumed for protein side-chains 19 .…”

Section: Protein Structure Setupmentioning

confidence: 99%

“…19 The incomplete light chain was capped before Glu1C with an ACE residue and after Ile14L with an NME residue. 19 The incomplete heavy chain was capped after Gly246 with an NME residue. 19 Missing residues Trp148, Thr149, Ala149A, Asn149B, Val149C, Gly149D, Lys149E in chain H were modeled in the structure using the FALC-Loop web server 21 .…”

Section: Protein Structure Setupmentioning

confidence: 99%

See 4 more Smart Citations

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

Calabró

Woods²,

Powlesland

et al. 2016

J. Phys. Chem. B

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Section: Protein Structure Setupmentioning

confidence: 99%

Section: Protein Structure Setupmentioning

confidence: 99%

Section: Protein Structure Setupmentioning

confidence: 99%

Section: Protein Structure Setupmentioning

confidence: 99%

Section: Protein Structure Setupmentioning

confidence: 99%

See 3 more Smart Citations

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

Calabró

Woods²,

Powlesland

et al. 2016

J. Phys. Chem. B

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3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Verma

Narendra

Raju

et al. 2022

Archiv der Pharmazie

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Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)‐approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D‐quantitative structure activity relationship (3D‐QSAR) model coupled with scaffold hopping. The 3D‐QSAR model was developed using reported indole‐2,3‐diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole‐2,3‐diones‐based compound, that is, cmp 3, was further considered for scaffold hopping. Two top‐ranked bioisosteres, that is, benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one, were selected for designing new inhibitors by considering the field pattern of 3D‐QSAR. All designed molecules were mapped perfectly on the 3D‐QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5–6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D‐QSAR result. The top five inhibitor‐ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02–0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

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Identification and study of new NF‐κB‐inducing kinase ligands derived from the imidazolone scaffold

Maqueda‐Zelaya,

Valiño‐Rivas,

Milián

et al. 2024

Archiv der Pharmazie

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Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology‐derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB‐inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF‐κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF‐κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF‐κB activation, confirming that the derivative bearing the 4‐pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK‐dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD.

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Rapid decomposition and visualisation of protein–ligand binding free energies by residue and by water

Cited by 81 publications

References 45 publications

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Identification and study of new NF‐κB‐inducing kinase ligands derived from the imidazolone scaffold

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