Theoretical Studies on the Inhibition Mechanism of Cyclooxygenase-2. Is There a Unique Recognition Site?

Soliva, Robert; Almansa, Carmen; Kalko, Susana G.; Luque, F. Javier; Orozco, Modesto

doi:10.1021/jm0209376

Cited by 49 publications

(55 citation statements)

References 46 publications

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“…The amide hydrogens of the sulphonamide group interact with the backbone of Phe518 via two water bridges. Unfortunately, x-rays have not been able to resolve the conformation of the sulphonamide group in the selectivity pocket, and conformations dissimilar to the x-rays' one have been already reported in previous theoretical studies (25,26).…”

Section: Resultsmentioning

confidence: 94%

Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

Limongelli

Bonomi

Marinelli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

195

179

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The widely used nonsteroidal anti-inflammatory drugs block the cyclooxygenase enzymes (COXs) and are clinically used for the treatment of inflammation, pain, and cancers. A selective inhibition of the different isoforms, particularly COX-2, is desirable, and consequently a deeper understanding of the molecular basis of selective inhibition is of great demand. Using an advanced computational technique we have simulated the full dissociation process of a highly potent and selective inhibitor, SC-558, in both COX-1 and COX-2. We have found a previously unreported alternative binding mode in COX-2 explaining the time-dependent inhibition exhibited by this class of inhibitors and consequently their long residence time inside this isoform. Our metadynamics-based approach allows us to illuminate the highly dynamical character of the ligand/protein recognition process, thus explaining a wealth of experimental data and paving the way to an innovative strategy for designing new COX inhibitors with tuned selectivity.nonsteroidal anti-inflammatory drugs | COX selectivity | coxibs | path collective variables | metadynamics N onsteroidal anti-inflammatory drugs (NSAIDs) are widely used as therapeutic agents for the treatment of pain and inflammation, and in addition several evidences have been very recently reported on their chemopreventive effect in colorectal cancer (1). Their mechanism of action is based on the blockage of the cyclooxygenase enzymes (COXs) (2) by sterically hindering the entrance of the physiological binder arachidonic acid. The classical NSAIDs such as aspirin, ibuprofen, or flurbiprofen are nonselective and inhibit indifferently all the COXs isoforms. In the last few decades, the interest of scientists has been mostly focused on a selective inhibition between COX-1/COX-2. In fact, the inhibition of COX-1, particularly in the gastrointestinal system, may lead to dangerous side effects such as ulcers. As a consequence, a selective inhibition of COX-2 has been sought for decades, and recently a new generation of NSAIDs, namely coxibs, was found. However, some of them, such as rofecoxib (Vioxx®), have been withdrawn from the market due to their cardiotoxicity (3-5). This was not the case of other COX-2 selective drugs such as celecoxib and nimesulide, with the latter one largely used as an anti-inflammatory agent in many diseases. As a consequence, today, in the rational design of new COXs binders, medicinal chemists have to pay attention to the selectivity properties of the designed drugs, and a fine-tuning of the COX selectivity profile might be necessary to generate novel effective drugs with reduced side effects. In the rational modulation of the binders selectivity precious help comes from the x-ray crystallography. In fact, the crystallographic structures show that selective and nonselective inhibitors generally bind in two different patterns. In COX-1, the space of the selectivity pocket is reduced due to the presence of Ile523, while in COX-2 the presence of Val523 augments the available space provid...

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Section: Resultsmentioning

confidence: 94%

Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

Limongelli

Bonomi

Marinelli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

195

179

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“…Robert et al demonstrated the binding mechanism of diferent NSAIDs (mainly celecoxib and rofecoxib analogues) to the cyclooxygenase active site of COX-2 based on molecular dynamics (MD) simulation and free energy calculation studies [37]. The MD simulation study carried out by using the homology model of human COX-2 also revealed similar binding mode of interaction of SC-558 as observed from crystallographic pose [33].…”

Section: Molecular Basis Of Inhibition Of Cyclooxygenase Enzymes and mentioning

confidence: 86%

“…To investigate the key residues involved in the interaction of NSAIDs with COX-2, the MD trajectories were analysed by using UBEXTRACT programme. For example, the UBEXTRACT analysis [37] indicated that mainly four residues (Arg120, Asn192, Leu352 and Arg513) made signiicant electrostatic interactions, whereas thirteen residues involved in van der Waals interaction with the SC-558 ( Figure 4B). The inspection of experimental data of valdecoxib suggested that the methyl group atached to the central isoxazole ring is favourable for binding by making hydrophobic interaction.…”

Section: Molecular Basis Of Inhibition Of Cyclooxygenase Enzymes and mentioning

confidence: 99%

“…The inspection of experimental data of valdecoxib suggested that the methyl group atached to the central isoxazole ring is favourable for binding by making hydrophobic interaction. The MD simulation study of rofecoxib [37] showed that the carbonyl group of furanone ring formed an H-bond with Ser530. It is interesting to note that to achieve this contact the side chain of Ser530 adopted a 'down orientation', whereas it favours 'up conformation' while interacting with celecoxib because of water-mediated H-bond between Ser530 and Tyr385 residues (Figure 5A and B).…”

Section: Molecular Basis Of Inhibition Of Cyclooxygenase Enzymes and mentioning

confidence: 99%

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Molecular Basis of Binding Interactions of NSAIDs and Computer-Aided Drug Design Approaches in the Pursuit of the Development of Cyclooxygenase-2 (COX-2) Selective Inhibitors

Deb¹,

Mailabaram²,

Al-Jaidi³

et al. 2017

Nonsteroidal Anti-Inflammatory Drugs

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The nonsteroidal anti-inlammatory drugs (NSAIDs) are important class of therapeutic agents used for the treatment of pain, inlammation and fever. Nonselective inhibition of cyclooxygenase (COX-1 and COX-2) isoenzymes by classical NSAIDs is associated with undesirable side efects such as gastrointestinal (GI) and renal toxicities due to COX-1 inhibition. To circumvent this problem, several COX-2 selective inhibitors were developed with superior GI safety proile. However, the voluntary market withdrawal of potent COX-2 selective inhibitors (rofecoxib and valdecoxib) due to their severe cardiovascular toxicity which is also found to be associated with some of the traditional NSAIDs suggesting the need to relook into the entire class of NSAIDs rather than exclusively victimizing the COX-2 selective inhibitors. Furthermore, the recent evidences for the involvement of COX-2 selective inhibitors in the aetiology of many diseases, such as Alzheimer's disease, Parkinson's disease, diabetes, various cancers and so on, have gained much atention for researchers to design and develop novel COX-2 selective inhibitors with improved pharmacodynamics and pharmacokinetic proile. This chapter is focused on the detailed analysis of molecular basis of binding interactions of various NSAIDs by highlighting the role of crucial amino acid residues at the binding site of cyclooxygenase enzymes (COXs) to be considered for selective inhibition of COX-2 enzyme while emphasising the impact of signiicant CADD strategies employed for designing new potent COX-2 inhibitors with tuned selectivity.

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“…The 6COX structure was chosen over 1CX2 (the same complex crystallized in a different space group) because it contains the correct conformation of the sulfonamide group relative to the connected aromatic ring, as demonstrated by simulation studies. 23,24 Structural manipulation was done in SYBYL 6.9 (Tripos, St. Louis, MO).…”

Section: Structure Preparationmentioning

confidence: 99%

Coupled atomic charge selectivity for optimal ligand‐charge distributions at protein binding sites

2006

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Charge optimization as a tool for both analyzing and enhancing binding electrostatics has become an attractive approach over the past few years. An interesting feature of this method for molecular design is that it provides not only the optimal charge magnitudes, but also the selectivity of a particular atomic center for its optimal charge. The current approach to compute the charge selectivity at a given atomic center of a ligand in a particular binding process is based on the binding-energy cost incurred upon the perturbation of the optimal charge distribution by a unit charge at the given atomic center, while keeping the other atomic partial charges at their optimal values. A limitation of this method is that it does not take into account the possible concerted changes in the other atomic charges that may incur a lower energetic cost than perturbing a single charge. Here, we describe a novel approach for characterizing charge selectivity in a concerted manner, taking into account the coupling between the ligand charge centers in the binding process. We apply this novel charge selectivity measure to the celecoxib molecule, a nonsteroidal anti-inflammatory agent binding to cyclooxygenase 2 (COX2), which has been recently shown to also exhibit cross-reactivity toward carbonic anhydrase II (CAII), to which it binds with nanomolar affinity. The uncoupled and coupled charge selectivity profiles over the atomic centers of the celecoxib ligand, binding independently to COX2 and CAII, are analyzed comparatively and rationalized with respect to available experimental data. Very different charge selectivity profiles are obtained for the uncoupled versus coupled selectivity calculations.

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Theoretical Studies on the Inhibition Mechanism of Cyclooxygenase-2. Is There a Unique Recognition Site?

Cited by 49 publications

References 46 publications

Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

Molecular Basis of Binding Interactions of NSAIDs and Computer-Aided Drug Design Approaches in the Pursuit of the Development of Cyclooxygenase-2 (COX-2) Selective Inhibitors

Coupled atomic charge selectivity for optimal ligand‐charge distributions at protein binding sites

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