Rapid and Accurate Estimation of Protein-Ligand Relative Binding Affinities using Site-Identification by Ligand Competitive Saturation

Predicting relative protein-ligand binding affinities is a central pillar of lead optimization efforts in structure-based drug design. The Site Identification by Ligand Competitive Saturation (SILCS) methodology is based on functional...

Download Full-text

Computational methods for calculation of protein-ligand binding affinities in structure-based drug design

Physical Sciences Reviews ◽

10.1515/psr-2020-0034 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Zbigniew Dutkiewicz

Keyword(s):

Drug Design ◽

Ligand Binding ◽

Binding Free Energy ◽

Development Project ◽

Quantum Mechanical ◽

Prediction Methods ◽

Binding Affinities ◽

Structure Based Drug Design ◽

Quantum Mechanical Description ◽

Optimization Stage

AbstractDrug design is an expensive and time-consuming process. Any method that allows reducing the time the costs of the drug development project can have great practical value for the pharmaceutical industry. In structure-based drug design, affinity prediction methods are of great importance. The majority of methods used to predict binding free energy in protein-ligand complexes use molecular mechanics methods. However, many limitations of these methods in describing interactions exist. An attempt to go beyond these limits is the application of quantum-mechanical description for all or only part of the analyzed system. However, the extensive use of quantum mechanical (QM) approaches in drug discovery is still a demanding challenge. This chapter briefly reviews selected methods used to calculate protein-ligand binding affinity applied in virtual screening (VS), rescoring of docked poses, and lead optimization stage, including QM methods based on molecular simulations.

Download Full-text

Free Energy Calculations to Estimate Ligand-Binding Affinities in Structure-Based Drug Design

Current Pharmaceutical Design ◽

10.2174/13816128113199990604 ◽

2014 ◽

Vol 20 (20) ◽

pp. 3323-3337 ◽

Cited By ~ 38

Author(s):

M. Reddy ◽

C. Reddy ◽

R. Rathore ◽

Mark Erion ◽

P. Aparoy ◽

...

Keyword(s):

Free Energy ◽

Drug Design ◽

Ligand Binding ◽

Free Energy Calculations ◽

Binding Affinities ◽

Structure Based Drug Design ◽

Energy Calculations

Download Full-text

1 Computational methods for calculation of protein-ligand binding affinities in structure-based drug design

Theoretical and Computational Chemistry ◽

10.1515/9783110678215-001 ◽

2021 ◽

pp. 1-40

Author(s):

Zbigniew Dutkiewicz

Keyword(s):

Drug Design ◽

Ligand Binding ◽

Computational Methods ◽

Binding Affinities ◽

Structure Based Drug Design

Download Full-text

Large scale relative protein ligand binding affinities using non-equilibrium alchemy

Chemical Science ◽

10.1039/c9sc03754c ◽

2020 ◽

Vol 11 (4) ◽

pp. 1140-1152 ◽

Cited By ~ 19

Author(s):

Vytautas Gapsys ◽

Laura Pérez-Benito ◽

Matteo Aldeghi ◽

Daniel Seeliger ◽

Herman van Vlijmen ◽

...

Keyword(s):

Molecular Dynamics ◽

Drug Design ◽

Ligand Binding ◽

Large Scale ◽

Md Simulations ◽

Great Promise ◽

Binding Affinities ◽

Structure Based Drug Design ◽

Thermodynamic Cycles ◽

Binding Affinity Calculations

Relative ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design.

Download Full-text

Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

Frontiers in Neuroscience ◽

10.3389/fnins.2020.609005 ◽

2020 ◽

Vol 14 ◽

Author(s):

Thao N. T. Ho ◽

Nikita Abraham ◽

Richard J. Lewis

Keyword(s):

Drug Design ◽

Ligand Binding ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Molecular Mechanisms ◽

Rational Drug Design ◽

Comprehensive Overview ◽

Nicotinic Acetylcholine ◽

Structure Based Drug Design ◽

Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

Download Full-text