Contribution of Explicit Solvent Effects to the Binding Affinity of Small-Molecule Inhibitors in Blood Coagulation Factor Serine Proteases

ChemMedChem ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. 1049-1066 ◽  
Author(s):  
Robert Abel ◽  
Noeris K. Salam ◽  
John Shelley ◽  
Ramy Farid ◽  
Richard A. Friesner ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Binding Affinity ◽  
Small Molecule ◽  
Solvent Effects ◽  
Serine Proteases ◽  
Small Molecule Inhibitors ◽  
Coagulation Factor ◽  
Explicit Solvent

The Design of Competitive, Small-molecule Inhibitors of Coagulation Factor Xa

2004 ◽  
Vol 1 (1) ◽  
pp. 129-152 ◽  
Author(s):  
Henry W. Pauls ◽  
William R. Ewing ◽  
Yong M. Choi-Sledeski
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Factor Xa ◽  
Coagulation Factor

scholarly journals Entropy of Stapled Peptide Inhibitors in Free State is the Major Contributor to the Improvement of Binding Affinity

2021 ◽  
Author(s):  
Ilona Christy Unarta ◽  
Jianchao Xu ◽  
Yuan Shang ◽  
Carina Hey Pui Cheung ◽  
Ruichi Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Peptide Inhibitors ◽  
Major Contributor ◽  
Protein Targets ◽  
Stapled Peptide ◽  
Protein Protein Interaction ◽  
Energetic Interactions

Stapled peptides are promising protein-protein interaction (PPI) inhibitors that can increase binding potency. Different from small-molecule inhibitors in which binding mainly depends on energetic interactions with their protein targets, stapled...

scholarly journals Targeting dysregulation signatures of p53-MDM2 interactions to identify newer small molecule inhibitors for cancer therapy: Insight from computational direction

2021 ◽  
Author(s):  
Prosper Obed Chukwuemeka ◽  
Haruna Isiyaku Umar ◽  
Opeyemi Iwaloye ◽  
Oluwaseyi Matthew Oretade ◽  
Christopher Busayo Olowosoke ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Option ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Hydrogen Bond Acceptor ◽  
Potential Inhibitors

Abstract Dysregulation of the p53-MDM2 interactions has been implicated in majority of human tumors presenting a target for finding small molecule inhibitors. In this study, a training set of 17 experimentally tested inhibitors of MDM2 was used to develop series of pharmacophore models among which a four-featured (AHRR_1) model with one hydrogen bond acceptor, one hydrophobic group and two aromatic ring features and characterized by a survival score of 4.176 was considered significant among the top ranked generated hypothesis. Further, the model was validated by an external set of actives and decoy molecules and was found to exhibit encouraging statistical attributes (such as AUC > 0.7, BEDROC > 0.5 and EF > 1.0 etc). The model was used to screen the ZINC compound database, from the database, the top best 1375 hits satisfying the pharmacophore model was were docked to MDM2 protein to identify the likely interactions of the compounds as well as their binding affinity with MDM2. Further, druglikeness and pharmacokinetic properties screening on top-ranked compounds with higher binding affinity than reference inhibitors revealed four compounds (ZINC02639178, ZINC38933175, ZINC77969611, and ZINC06752762) with suitable pharmacological properties including low ligand toxicity. Investigation of the dynamic behaviour of each candidate inhibitors in complex with MDM2 via molecular dynamic simulation suggested ZINC02639178 and ZINC06752762 as the most potential inhibitors. Thus, these compounds may emerged as therapeutic option for cancer treatment after extensive in vitro and in vivo studies.

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