scholarly journals Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 74
Author(s):  
Justin Spiriti ◽  
Chung F. Wong
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Early Stage ◽  
Steered Molecular Dynamics ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Dissociation Kinetics ◽  
Binding Characteristics

Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power–law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

Kinetics of Drug Binding and Residence Time

2019 ◽  
Vol 70 (1) ◽  
pp. 143-171 ◽  
Author(s):  
Mattia Bernetti ◽  
Matteo Masetti ◽  
Walter Rocchia ◽  
Andrea Cavalli
Keyword(s):  
Computational Methods ◽  
Residence Time ◽  
Drug Target ◽  
Early Stage ◽  
Kinetic Constant ◽  
Theoretical Background ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Kinetics Of

The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/ koff). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy). There are many experimental and computational methods for predicting drug-target residence time at an early stage of drug discovery programs. Here, we review and discuss the methodological approaches to estimating drug binding kinetics and residence time. We first introduce the theoretical background of drug binding kinetics from a physicochemical standpoint. We then analyze the recent literature in the field, starting from the experimental methodologies and applications thereof and moving to theoretical and computational approaches to the kinetics of drug binding and unbinding. We acknowledge the central role of molecular dynamics and related methods, which comprise a great number of the computational methods and applications reviewed here. However, we also consider kinetic Monte Carlo. We conclude with the outlook that drug (un)binding kinetics may soon become a go/no go step in the discovery and development of new medicines.

scholarly journals Focal adhesion kinase inhibitors, a heavy punch to cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yueling Wu ◽  
Ning Li ◽  
Chengfeng Ye ◽  
Xingmei Jiang ◽  
Hui Luo ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Perspective View ◽  
Combination Strategy ◽  
Cancer Cell Growth ◽  
Cancer Types ◽  
Chemotherapy Strategy

AbstractKinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

scholarly journals Molecular Dynamics of A Biglycan-Rosmarinic Acid Complex with Focal Adhesion Kinase for Possible Arrest of Metastasis in Non-Small Cell Lung Cancer (NSCLC): An In- Silico Study

2019 ◽  
Vol 9 (4-A) ◽  
pp. 159-166
Author(s):  
Hyacinth Highland ◽  
Monica Thakur ◽  
Pujan Pandya ◽  
Archana Mankad ◽  
Linz-Buoy George
Keyword(s):  
Lung Cancer ◽  
Molecular Dynamics ◽  
Molecular Docking ◽  
Small Cell Lung Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Lung Cancer ◽  
Rosmarinic Acid ◽  
Small Cell ◽  
Small Cell Lung

Background: Non-small cell lung cancer (NSCLC) is the major cause of mortality all over the world. Significant increase of biglycan is seen in the lung cancer cells when compared with the normal cells. It promotes tumor invasion and metastasis by activating Focal Adhesion Kinase (FAK) signaling pathway. The increased FAK activity may contribute to the metastatic potential of malignant tumors. This study was carried out to establish binding interactions of some selected phytocomponents against biglycan for the possible arrest of metastasis. Methods: Protein-ligand interaction studies were performed using 30 natural compounds from different culinary herbs having potential therapeutic role against the target protein biglycan (BGN). Molegro Virtual Docker (v 5.0) was used as docking tool to evaluate the effectiveness of selected phytocomponents based upon the interaction with the protein’s active site residues with minimal binding energy. Protein-protein docking was performed to observe the interaction of BGN and FAK using Hex (v 8.0.0). Molecular dynamics (10 ns) of BGN-RA-FAK and FAK-RA-BGN was performed in Yasara structure (v 17.8.15) which showed stability of the structure in terms of RMSD values. Results: Molecular docking analysis revealed the selectivity of Rosmarinic acid (RA) towards BGN and FAK. Molecular dynamics trajectory of BGN-RA-FAK and FAK-RA-BGN complexes showed the stability of structure in terms of Time vs Energy and Time vs RMSD values and revealed that binding of RA to BGN will block the interaction of FAK. Conclusions: Hence, investigating the binding interactions of BGN-RA-FAK complex may turn out to be helpful in arresting metastasis in NSCLC. Keywords: Non-small cell lung cancer, Biglycan, Focal adhesion kinase, Phytocomponents, Molecular Docking, Molecular Dynamics

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