Pharmacophore elucidation and 3D-QSAR analysis of a new class of highly potent inhibitors of acid ceramidase based on maximum common substructure and field fit alignment methods

Pirhadi, Somayeh; Shiri, Fereshteh; Ghasemi, Jahan B.

doi:10.1007/s13738-013-0402-6

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…With introduction of comparative molecular eld analysis (CoMFA) 211 in 1988 for the rst time, structure-activity relationships were presented based on the three-dimensional structure of the molecules (3D-QSAR). 212,213 In this way, a series of compounds superimposed in 3D space are placed onto a surface or grid which mimics the binding site of the true biological receptor. Ligands' interaction with chemical probes is then gathered as descriptors.…”

Section: Nd-qsar Methodsmentioning

confidence: 99%

Multivariate statistical analysis methods in QSAR

2015

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Section: Nd-qsar Methodsmentioning

confidence: 99%

Multivariate statistical analysis methods in QSAR

2015

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“…Overall, designing inhibitors for targets with amino acid mutations addresses drug resistance, improves selectivity, and uncovers new therapeutic opportunities, leading to more effective and targeted treatments for various diseases [ 20 , 21 ]. The utilization of computer-aided drug design (CADD) methods offers several advantages in the drug development process, including the reduction of time and costs involved and an enhanced likelihood of achieving successful outcomes [ 22 , 23 ]. Virtual screening (VS) has shown significant success rates in computationally screening libraries of molecules to discover hits.…”

Section: Introductionmentioning

confidence: 99%

Hit discovery of potential CDK8 inhibitors and analysis of amino acid mutations for cancer therapy through computer-aided drug discovery

Aghahasani,

Shiri,

Kamaladiny

et al. 2024

BMC Chemistry

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Cyclin-dependent kinase 8 (CDK8) has emerged as a promising target for inhibiting cancer cell function, intensifying efforts towards the development of CDK8 inhibitors as potential cancer therapeutics. Mutations in CDK8, a protein kinase, are also implicated as a primary factor associated with tumor formation. In this study, we identified potential inhibitors through virtual screening for CDK8 and single amino acid mutations in CDK8, namely D173A (Aspartate 173 mutate to Alanine), D189N (Aspartate 189 mutate to Asparagine), T196A (Threonine 196 mutate to Alanine) and T196D (Threonine 196 mutate to Aspartate). Four databases (CHEMBEL, ZINC, MCULE, and MolPort) containing 65,209,131 molecules have been searched to identify new inhibitors for CDK8 and its single mutations. In the first step, structure-based pharmacophore modeling in the Pharmit server was used to select the compounds to know the inhibitors. Then molecules with better predicted drug-like molecule properties were selected. The final filter used to select more effective inhibitors among the previously selected molecules was molecular docking. Finally, 13 hits for CDK8, 11 hits for D173A, 11 hits for D189N, 15 hits for T196A, and 12 hits for T196D were considered potential inhibitors. A majority of the virtual screening hits exhibited satisfactorily predict pharmacokinetic characteristics and toxicity properties.

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“…In the QSPR/QSAR theory, the ultimate goal is to develop mathematical models for the estimation of relevant properties and chemical and biological activities of interest (Pirhadi et al, 2014). It is important especially in cases where they cannot be experimentally determined.…”

Section: Introductionmentioning

confidence: 99%

Alignment independent 3D-QSAR, quantum calculations and molecular docking of Mer specific tyrosine kinase inhibitors as anticancer drugs

Shiri

Pirhadi

Ghasemi

2016

Saudi Pharmaceutical Journal

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Mer receptor tyrosine kinase is a promising novel cancer therapeutic target in many human cancers, because abnormal activation of Mer has been implicated in survival signaling and chemoresistance. 3D-QSAR analyses based on alignment independent descriptors were performed on a series of 81 Mer specific tyrosine kinase inhibitors. The fractional factorial design (FFD) and the enhanced replacement method (ERM) were applied and tested as variable selection algorithms for the selection of optimal subsets of molecular descriptors from a much greater pool of such regression variables. The data set was split into 65 molecules as the training set and 16 compounds as the test set. All descriptors were generated by using the GRid INdependent descriptors (GRIND) approach. After variable selection, GRIND were correlated with activity values (pIC50) by PLS regression. Of the two applied variable selection methods, ERM had a noticeable improvement on the statistical parameters of PLS model, and yielded a q (2) value of 0.77, an [Formula: see text] of 0.94, and a low RMSEP value of 0.25. The GRIND information contents influencing the affinity on Mer specific tyrosine kinase were also confirmed by docking studies. In a quantum calculation study, the energy difference between HOMO and LUMO (gap) implied the high interaction of the most active molecule in the active site of the protein. In addition, the molecular electrostatic potential energy at DFT level confirmed results obtained from the molecular docking. The identified key features obtained from the molecular modeling, enabled us to design novel kinase inhibitors.

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Pharmacophore elucidation and 3D-QSAR analysis of a new class of highly potent inhibitors of acid ceramidase based on maximum common substructure and field fit alignment methods

Cited by 9 publications

References 21 publications

Multivariate statistical analysis methods in QSAR

Multivariate statistical analysis methods in QSAR

Hit discovery of potential CDK8 inhibitors and analysis of amino acid mutations for cancer therapy through computer-aided drug discovery

Alignment independent 3D-QSAR, quantum calculations and molecular docking of Mer specific tyrosine kinase inhibitors as anticancer drugs

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