CHARMM force field parameterization of rosiglitazone (original) (raw)
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CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands
International journal of molecular sciences, 2016
The peroxisome proliferator-activated receptor γ (PPARγ) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPARγ ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPARγ partial agonist that has been shown to promote the "browning" of white adipose tissue. SR1664 is the precursor of the PPARγ non-agonist class of ligands that activates PPARγ in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were eval...
Journal of Biomolecular Structure and Dynamics, 2020
Type 2 diabetes (T2D) is generally characterized by elevated blood glucose level, insulin resistance, and relative lack of insulin, however, insulin resistance is the predominant risk factor. Hence, the use of insulin sensitizer drugs to increase insulin sensitivity have gained immense interest as an attractive treatment option for T2D and their major target is a nuclear receptor PPAR-γ (peroxisome proliferator-activated receptor-γ). A wide range of synthetic insulin sensitizers such as thiazolidinedione act as PPAR-γ agonists thereby enhancing insulin action and improving hyperglycemia in patients. Nonetheless, they pose severe adverse effects for human, necessitating an emergent need to develop effective insulin sensitizer drugs. Herein, virtual screening of 10,000 ligands is performed and the best five ligands are identified. MET364, ILE341, CYS285, ALA292, PHE282, and LEU330 residues are found to play an important role in ligand binding. It is shown from the molecular dynamics simulations results of the top-ranked ligands that increased numbers of hydrogen bonds are formed with PPAR-γ catalytic residues. Quantum chemical calculations reveal that all the best ligands can demonstrate good thermodynamic stability and pharmacokinetic properties. Partial-leastsquare (PLS) regression of quantitative structural activity relationship (QSAR) is utilized to model and predict the binding energy for ligands. Principal component analysis is further explored for the best ligands' QSAR pattern recognition. Importantly, the predicted values of the binding energy of the potential ligands by the PLS regression is favourably compared with the values of binding energy obtained from molecular docking with incredible high accuracy of 98%.
X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs
Biochim Biophys Acta Gen Subj, 2017
Thiazolidinedione (TZD) compounds targeting the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) demonstrate unique benefits for the treatment of insulin resistance and type II diabetes. TZDs include rosiglitazone, pioglitazone and rivoglitazone, with the latter being the most potent. The TZDs are only marginally selective for the therapeutic target PPARγ as they also activate PPARα and PPARδ homologues to varying degrees, causing off-target effects. While crystal structures for TZD compounds in complex with PPARγ are available, minimal structural information is available for TZDs bound to PPARα and PPARδ. This paucity of structural information has hampered the determination of precise structural mechanisms involved in TZD selectivity between PPARs. To help address these questions molecular dynamic simulations were performed of rosiglitazone, pioglitazone and rivoglitazone in complex with PPARα, PPARδ, and PPARγ in order to better understand the mechanisms of PPAR selectivity. The simulations revealed that TZD interactions with residues Tyr314 and Phe318 of PPARα and residues Phe291 and Thr253 of PPARδ as well as the omega loop, are key determinants of TZD receptor selectivity. Notably, in this study, we solve the first X-ray crystal structure of rivoglitazone bound to any PPAR. Rivoglitazone forms a unique hydrogen bond network with the residues of the PPARγ co-activator binding surface (known as AF2) and makes more extensive contacts with helix 3 and the β- sheet as compared to model TZD compounds such as rosiglitazone.
In silico modelling and molecular dynamics simulation studies of thiazolidine based PTP1B inhibitors
Journal of biomolecular structure & dynamics, 2017
Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signalling pathway, hence it can be considered as a new therapeutic target of intervention for the treatment of type2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e., diabestiy. In order to get more information on identification and optimisation of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold. A six-point pharmacophore model consisting of three hydrogen bond acceptor (A), one negative ionic (N) and two aromatic rings (R) with discrete geometries as pharmacophoric features were developed for a predictive 3D QSAR model. The probable binding conformation of the ligands within the active site was studied through molecular docking. The molecular interactions and the structural features responsible for PTP1B inhibition and selecti...
Journal of Biomolecular Structure and Dynamics, 2019
Diabetes is a foremost health problem globally susceptible to increased mortality and morbidity. The present therapies in the antidiabetic class have sound adverse effects and thus, emphasis on the further need to develop effective medication therapy. Peroxisome proliferator-activated receptor alpha-gamma dual approach represents an interesting target for developing novel anti-diabetic drug along with potential anti-hyperlipidimic activity. In the current study, the peroxisome proliferator-activated receptor alpha-gamma agonistic hits were screened by hierarchical virtual screening of drug like compounds followed by molecular dynamics simulation and knowledge-based structure-activity relation analysis. The key amino acid residues of binding pockets of both target proteins were acknowledged as essential and were found to be associated in the key interactions with the most potential dual hit. This dual targeted approach of structure based computational technique was undertaken to identify prevalent promising hits for both targets with binding energy and absorption distribution metabolism excretion prediction supported the analysis of their pharmacokinetic potential. In addition, stability analysis using molecular dynamics simulation of the target protein complexes was performed with the most promising dual targeted hit found in this study. Further, comparative analysis of binding site of both targets was done for the development of knowledge-based structure-activity relationship, which may useful for successful designing of dual agonistic candidates.
International Journal of Pharmacy and Pharmaceutical Sciences, 2016
Objectives: Thiazolidinediones a promising and privileged scaffold in medicinal chemistry that has been popularly recognized for its antidiabetic activity. The objective of the current study is to explore the effects of substitution replacing the acidic hydrogen of thiazolidinedione ring. Methods: The protocol adopted was (i) In silico enumeration of small chemical library, (ii) molecular docking simulation and (iii) selection of hits based on predicted ADME/TOX properties to support further synthetic enumeration of chemical compounds for biological evaluation. Results: The results of the present study showed that all the designed compounds were found to be potent PPARγ modulators and shows promising lead like properties from the calculated ADME/TOX parameters. Rosiglitazone was taken as a standard for the comparison of In silico studies. Conclusion: The design strategy adopted has predicted improved potency, less toxicity and a better binding mode prediction towards PPARγ.
Journal of Bionanoscience, 2016
Chronic myeloid leukemia (CML), a hematological malignancy arises due to the spontaneous fusion of the BCR and ABL gene, resulting in a constitutively active tyrosine kinase (BCR-ABL). Pharmacological activity of Gallic acid and 1,3,4-Oxadiazole as potential inhibitors of ABL kinase has already been reported. Objective of this study is to evaluate the ABL kinase inhibitory activity of derivatives of Gallic acid fused with 1,3,4-Oxadiazole moieties. Attempts have been made to identify the key structural features responsible for drug likeness of the Gallic acid and the 1,3,4-Oxadiazole ring using molecular electrostatic potential maps (MESP). To investigate the inhibitory activity of Gallic acid derivatives towards the ABL receptor, we have applied molecular docking and molecular dynamics (MD) simulation approaches. A comparative study was performed using Bosutinib as the standard which is an approved CML drug acting on the same receptor. Furthermore, the novel compounds designed and reported here in were evaluated for ADME properties and the results indicate that they show acceptable pharmacokinetic properties. Accordingly these compounds are predicted to be drug like with low toxicity potential.
Journal of Pharmaceutical Chemistry, 2017
Peroxisome proliferated receptors (PPARs) are important targets for drugs used in the treatment of various metabolic disorders. We have reported 4-hydroxy benzylidene derivatives of thiazolidine-2,4-diones with reversed orientation in the active site of PPARγin our earlier communication. With the reversed conformation of TZD, fitting the established pharmacophore was discussed. The current simulation studies revolves around the 2,4-dihydroxy benzylidene derivatives expecting H-bonding interactions similar to Rosiglitazone’s acidic head. The docking protocol was validated by enrichment studies using decoys and actives from DUD. Designed compounds were showing interactions similar to the actives in the top 10%, 5% and 1%. They also exhibited H-bonding interactions similar to their monohydroxy counterparts without any additional H-bonding interactions due to introduction of additional hydroxy functional groups. Predicted ADMET report reveals that 5 molecules show favourable hERG-I a...
International Journal of Molecular Sciences, 2015
The structural and dynamical properties of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor have been broadly studied in its agonist state but little is known about the key features required for the receptor antagonistic activity. Here we report a series of molecular dynamics (MD) simulations in combination with free energy estimation of the recently discovered class of non-covalent PPARγ antagonists. Their binding modes and dynamical behavior are described in details. Two key interactions have been detected within the cavity between helices H3, H11 and the activation helix H12, as well as with H12. The strength of the ligand-amino acid residues interactions has been analyzed in relation to the specificity of the ligand dynamical and antagonistic features. According to our results, the PPARγ activation helix does not undergo dramatic conformational changes, as seen in other nuclear receptors, but rather perturbations that occur through a significant ligand-induced reshaping of the ligand-receptor and the receptor-coactivator binding pockets. The H12 residue Tyr473 and the charge clamp residue Glu471 play a central role for the receptor transformations. Our results also demonstrate that MD can be a helpful tool for the compound phenotype characterization (full agonists, partial agonists or antagonists) when insufficient experimental data are available.