A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA. A homology model of HERG was constructed from the crystal structure of the open MthK potassium channel. A complementary relationship between our CoMSiA and homology models is apparent when the long inhibitor axis is oriented parallel to the longitudinal axis of the pore, with the tail region pointed toward the selectivity filter. The key elements of the pharmacophore, the CoMSiA and the homology model are: (1) The hydrophobic feature optimally consists of an aromatic group that is capable of engaging in pi-stacking with a Phe656 side chain. Optionally, a second aromatic or hydrophobic group present in some inhibitors may contact an additional Phe656 side chain. (2) The basic nitrogen appears to undergo a pi-cation interaction with Tyr652. (3) The pore diameter (12A+), and depth of the selectivity loop relative to the intracellular opening, act as constraints on the conformation-dependent inhibitor dimensions.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/s0960-894x(03)00196-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Virtual screening of PEBP1 inhibitors by combining 2D/3D-QSAR analysis, hologram QSAR, homology modeling, molecular docking analysis, and molecular dynamic simulations.
J Mol Model
May 2022
Laboratory of Natural Substances, Pharmacology, Environment, Modeling, Health & Quality of Life (SNAMOPEQ), Polydisciplinary Faculty of Taza, Sidi Mohamed Ben Abdellah University of Fez, Taza Gare, B.P 1223, Taza, Morocco.
Human phosphatidylethanolamine binding protein 1 (hPEBP1) is a novel target affecting many cellular signaling pathways involved in the formation of metastases. It can be used in the treatment of many cases of cancer. For these reasons, pharmaceutical companies use computational approaches, including multi-QSAR (2D, 3D, and hologram QSAR) analysis, homology modeling, molecular docking analysis, and molecular dynamic simulations, to speed up the drug discovery process.
View Article and Find Full Text PDFTheoretical Exploring Selective-Binding Mechanisms of JAK3 by 3D-QSAR, Molecular Dynamics Simulation and Free Energy Calculation.
Front Mol Biosci
May 2020
School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
Janus kinase 3 (JAK3) plays a critical role in the JAK/STAT signaling pathway and has become an attractive selective target for the treatment of immune-mediated disorders. Therefore, great efforts have been made for the development of JAK3 inhibitors, but developing selective JAK3 inhibitors remains a great challenge because of the high sequence homology with other kinases. In order to reveal the selective-binding mechanisms of JAK3 and to find the key structural features that refer to specific JAK3 inhibition, a systematic computational method, including 3D-QSAR, molecular dynamics simulation, and free energy calculations, was carried out on a series of JAK3 isoform-selective inhibitors.
View Article and Find Full Text PDFQuantitative structure-activity relationships analysis, homology modeling, docking and molecular dynamics studies of triterpenoid saponins as Kirsten rat sarcoma inhibitors.
J Biomol Struct Dyn
January 2021
Materials, Natural Substances, Environment and Modeling Laboratory (LMSNEM), Polydisciplinary Faculty of Taza, Sidi Mohamed Ben Abdellah University of Fez, Taza, Morocco.
Oncogenic Kirsten RAt Sarcoma (KRAS) mutations are attractive targets in non-small-cell lung cancer (NSCLC). Thus, the objective of this work is to discover promising inhibitors that target this protein using methods that have become increasingly cost-effective in research and development of drugs. In this study, 24 triterpenoid saponins were selected for designing the potent inhibitors using different methods: quantitative structure activity relationships (QSAR) analysis, homology modeling, as well as molecular docking, molecular dynamics (MD) simulation and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) screening.
View Article and Find Full Text PDFHomology modeling and 3D-QSAR study of benzhydrylpiperazine δ opioid receptor agonists.
Comput Biol Chem
December 2019
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
The binding affinity of a series of benzhydrylpiperazine δ opioid receptor agonists were pooled and evaluated by using 3D-QSAR and homology modeling/molecular docking methods. Ligand-based CoMFA and CoMSIA 3D-QSAR analyses with 46 compounds were performed on benzhydrylpiperazine analogues by taking the most active compound BW373U86 as the template. The models were generated successfully with q value of 0.
View Article and Find Full Text PDFInsight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.
J Mol Model
March 2018
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, China.
Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r) were 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!