In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor γ agonists

Paliwal, Sarvesh; Yadav, Divya; Yadav, Rakesh; Paliwal, Sunil

doi:10.1007/s00044-010-9370-x

Cited by 7 publications

(4 citation statements)

References 21 publications

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“…The receptor active site was identified using a sphere whose location and radius was adjusted to 9.0 Å, so as to include the active site and the key residues of the protein involved in interaction with ligands. Keeping the density of lipophilic sites and density of polar sites parameter value to 10, the interaction map was generated [34] .…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel HIV 1- Protease Inhibitors: Application of Ligand and Structure Based Pharmacophore Mapping and Virtual Screening

et al. 2012

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A combined ligand and structure-based drug design approach provides a synergistic advantage over either methods performed individually. Present work bestows a good assembly of ligand and structure-based pharmacophore generation concept. Ligand-oriented study was accomplished by employing the HypoGen module of Catalyst in which we have translated the experimental findings into 3-D pharmacophore models by identifying key features (four point pharmacophore) necessary for interaction of the inhibitors with the active site of HIV-1 protease enzyme using a training set of 33 compounds belonging to the cyclic cyanoguanidines and cyclic urea derivatives. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, two hydrogen bond acceptors and two hydrophobic, showed a correlation (r) of 0.90 and a root mean square of 0.71 and cost difference of 56.59 bits between null cost and fixed cost. The model was validated using CatScramble technique, internal and external test set prediction. In the second phase of our study, a structure-based five feature pharmacophore hypothesis was generated which signifies the importance of hydrogen bond donor, hydrogen bond acceptors and hydrophobic interaction between the HIV-1 protease enzyme and its inhibitors. This work has taken a significant step towards the full integration of ligand and structure-based drug design methodologies as pharmacophoric features retrieved from structure-based strategy complemented the features from ligand-based study hence proving the accuracy of the developed models. The ligand-based pharmacophore model was used in virtual screening of Maybridge and NCI compound database resulting in the identification of four structurally diverse druggable compounds with nM activities.

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Section: Methodsmentioning

confidence: 99%

Identification of Novel HIV 1- Protease Inhibitors: Application of Ligand and Structure Based Pharmacophore Mapping and Virtual Screening

et al. 2012

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“…The protein structure was monitored [7] for valence and the missing hydrogens were added, the structure was further checked using protein health check tool for any structural error. The cleaned enzyme structure was subjected to active site identification.…”

Section: Structure-based Pharmacophore Modelingmentioning

confidence: 99%

AchE-OGT dual inhibitors: Potential Partners in Handling Alzheimer’s Disease

Sharma

Jainarayanan

2018

Preprint

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The emerging role of O-GlcNAc Transferase (OGT) and tau protein in Alzheimer's disease (AD) holds promises for the treatment of this life-threatening neurodegenerative disorder. In view of the availability of 3D structure of OGT, we attempted to develop structure-based pharmacophore model to elucidate specific structural requirements for binding of inhibitors to the active site of OGT.During the course of study we discovered that donepezil, an old and trusted Acetylcholinesterase (AchE) inhibitor also possess the pharmacophoric sites important for interaction with OGT active site. To further explore the specific interactions of donepezil with OGT, we performed molecular docking studies using CDocker. The results of molecular docking and structure-based pharmacophore mapping revealed that donepezil has the required structural features to interact with various OGT active site amino acids like Lys842, His920, Leu653, Gly654, Asn838, and Thr921 in addition to its AchE interaction abilities. Our findings could be an important breakthrough in the design of OGT specific and/or AchE OGT dual inhibitors.

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“…Despite the adverse effects of current medications, development of new PPAR agonists are still of great interest because of the unique and promising feature of this class of drug, including the ability to directly target insulin resistance and provide a more durable glycemic (HbA1c) control when compared to other antidiabetic medications [33]. In an attempt to reduce the reverse effects, alternative approaches were considered to target the PPAR receptors including partial PPARγ agonists [34][35][36][37][38][39][40][41][42][43][44], multitargeted cooperative PPARα/γ dual agonists [28,31,40,[45][46][47][48][49][50][51][52][53][54][55][56][57][58], and PPARα/β/γ pan-agonists [30,35,[59][60][61][62][63][64][65].…”

Section: Introductionmentioning

confidence: 99%

To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

et al. 2020

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Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ (-144.6 kcal/mol), followed by hPPARα (-138.0 kcal/mol) and hPPARβ (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.

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In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor γ agonists

Cited by 7 publications

References 21 publications

Identification of Novel HIV 1- Protease Inhibitors: Application of Ligand and Structure Based Pharmacophore Mapping and Virtual Screening

Identification of Novel HIV 1- Protease Inhibitors: Application of Ligand and Structure Based Pharmacophore Mapping and Virtual Screening

AchE-OGT dual inhibitors: Potential Partners in Handling Alzheimer’s Disease

To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

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