Exploring structural requirement, pharmacophore modeling, and de novo design of LRRK2 inhibitors using homology modeling approach (original) (raw)
Related papers
Parkinson's results from the degeneration of dopamine-producing nerve cells in the brain, specifically in the substantia nigra and the locus coeruleus. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement ( akinesia ). Drug designing, one of the hottest topics have found its new pathway to create a history in the field of medical science. The lead compound analysis starts with CADD, assisting to identify and to optimize the right compound. The technique helps in generating a suitable compound specific to the disease; thereby an effective treatment is achieved. Molecular modeling method has been used for modeling a new molecule for Parkinson's using Carbidopa , a drug that's already designed. This drug is drawn using hyperchem, and its R group is modified by replacing different functional groups like CL, F, CF 2 OH, CCL 2 OH, NH 2 , CF 3, CH 2 CH 3, OH, and I its place and docked by using gold software. The molecules designed as such are optimized using different algorithms and their affinity is checked with protein. The binding free energy of the protein is calculated by performing docking process. The molecule with minimum binding energy will have the maximum binding affinity. The binding free energy is calculated by the formula Z = Sum of the energy of optimized ligand devoid of solvation parameters and the energy of the protein -ligand optimization.
World Research Journal of Pharma Technology, 2017
Drug design is also called as rational drug design or simply rational design. For the process of drug development, to fulfil these challenges, many multidisciplinary approaches are required and these approaches would form the basis of rational drug design. Molecular docking algorithms execute quantitative predictions of binding energetic which provide rankings of docked compounds which is based on the binding affinity of ligand-receptor complexes.
Asian Journal of Pharmaceutical and Clinical Research, 2018
Objective: Mechanistic study of newly reported anti-Parkinson agents by molecular docking to predict possible target. Methods: Structures of newer drugs known anti-Parkinson agents were drawn using ChemBioDraw 2D software. Thereafter, they were converted to 3D structures using ChemBioDraw 3D software in which they were subjected to energy minimization using the MM2 method and then saved as PDB extension files, which can be accessed using the AutoDock Vina (ADT) interface. ADT 1.5.6 software version was used for molecular docking study. Results: Various molecular targets were selected (D2/D3, D2, A2A, and MAO-B) and studied for Pardoprunox, Istradefylline, Rasagiline, and Bromocriptine. Pardoprunox, Istradefylline, and Bromocriptine had more affinity with their corresponding receptor with −6.9, −8.5, and −9.4 kcal/mol binding affinity, respectively, except Rasagiline, who has less affinity with its corresponding receptor (−6.4kcal/mol) and shown better affinity with 3pbl receptor (−6.7 kcal/mol). Conclusion: Pardoprunox, Istradefylline, and Bromocriptine were found to act on D2/D3 (3pbl), A2A (3pwh), and D2 (4yyw), respectively, whereas Rasagiline found to be act on D2/D3 (3pbl) receptor. The results help in prediction of mechanism and interaction to various Parkinson's disease targets.
Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors
Bioinformation, 2011
Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest Gb. On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.
Computer-aided drug design applied to Parkinson targets
Current neuropharmacology, 2017
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Although the scientific community has performed great efforts in the study of PD, and from the most diverse points of view, the disease remains incurable. The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial dysfunction and inflammation are thought to play major roles in the etiology. Current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate, and new therapeutic agents are much needed. In this review, recent advances in computer-aided drug design for the rational design of new compounds against Parkinson disease; using methods such as Quantitative Structure-Activity Relationships (QSAR), molecular docking, molecular dynamics and pharmacophore modeling are discussed. In this review, four targ...
The development of CNS-active LRRK2 inhibitors using property-directed optimisation
Bioorganic & Medicinal Chemistry Letters, 2013
Mutations in PARK8/LRRK2 are the most common genetic cause of Parkinson's disease. Inhibition of LRRK2 kinase activity has neuroprotective benefits, and provides a means of addressing the underlying biochemical cause of Parkinson's disease for the first time. Initial attempts to develop LRRK2 inhibitors were largely unsuccessful and highlight shortcomings intrinsic to traditional, high throughput screening methods of lead discovery. Recently, amino-pyrimidine GNE-7915 was reported as a potent (IC 50 = 9 nM) selective (1/187 kinases), brain-penetrant and non-toxic inhibitor of LRRK2. The use of in silico modelling, extensive in vitro assays and resource-efficient in vivo techniques to produce GNE-7915, reflects a trend towards the concerted optimisation of potency, selectivity and pharmacokinetic properties in early-stage drug development.
Structural characterization of LRRK2 Inhibitors
Journal of medicinal chemistry, 2015
Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported, but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a structure-function analysis of such inhibitors we mutated the active site of Dictyostelium Roco4 kinase to resemble LRRK2. Here, we show Saturation Transfer Difference (STD) NMR and the first co-crystal structures of two potent in vitro inhibitors, LRRK2-IN-1 and Compound19, with mutated Roco4. Our data demonstrate that this system can serve as excellent tool for the structural characterization and optimization of LRRK2 inhibitors using X-ray crystallography and NMR spectroscopy.
Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease
Journal of medicinal chemistry, 2018
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A adenosine receptor (AAR) and monoamine oxidase B (MAO-B). Twenty-four compounds that were among the highest ranked for both binding sites were evaluated experimentally, resulting in the discovery of four dual-target ligands. The most potent compound was an AAR antagonist with nanomolar affinity ( K = 19 nM) and inhibited MAO-B with an IC of 100 nM. Optimization guided by the predicted binding modes led to the identification of a second potent dual-target scaffold...
Molecules (Basel, Switzerland), 2018
The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The co...