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 77 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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show abstract

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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Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Abdullahi

Olotu

Soliman

2018

J of Cellular Biochemistry

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacteria that has gained wide recognition for its causative role in the development of various immune diseases, which includes localized aggressive periodontitis. Its ability to evade host defense mechanisms is mediated by the secretion of leukotoxin (LtxA), which induces death of white blood cells (leukocytes) by specific binding to their surface-expressed leukocyte function-associated receptor (LFA-1) in its active state. Therapeutic compounds that interfere with this pathogenic process and abrogate A. actinomycetemcomitans virulence have been reported in literature. These include doxycycline, and more recently phytochemical compounds such as hamamelitanin, resveratrol, naringin, and quercetin. However, the question remains how do they work? Therefore, with the aid of computational tools, we explore the molecular mechanisms by which they possibly elicit their therapeutic functions. Molecular mechanics Poisson/Boltzmann surface area analyses revealed that these compounds bind favorably to active LFA-1 with high affinity and considerable stability, indicative of their ability to occupy the LtxA binding site (LBS) and prevent LtxA binding. The conformational transition of open LFA-1 to its closed state further describe the mechanistic activity of these compounds. In addition to notable reductions in structural mobility and flexibility, the burial of surface-exposed interactive side chains at the LBS was observed, an occurrence that could alter the complementary binding of LtxA. It is also important to mention that these occurrences were induced more prominently by the phytochemicals. We believe that these findings will enhance the scope of drug design and discovery for potent LtxA antagonists with improved activities and therapeutic efficacies in the treatment of virulent A. actinomycetemcomitans diseases.

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

Cited by 77 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

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

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