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

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.

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

2014 ◽  
Vol 20 (20) ◽  
pp. 3323-3337 ◽  
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

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

2021 ◽  
Author(s):  
Himanshu Goel ◽  
Anthony Hazel ◽  
Vincent D. Ustach ◽  
Sunhwan Jo ◽  
Wenbo Yu ◽  
...  
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Lead Optimization ◽  
Accurate Estimation ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Relative Binding ◽  
Central Pillar ◽  
Site Identification

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...

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

2020 ◽  
Vol 11 (4) ◽  
pp. 1140-1152 ◽  
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.

A Perspective on Water Site Prediction Methods for Structure Based Drug Design

2017 ◽  
Vol 17 (23) ◽  
Author(s):  
Alan P. Graves ◽  
Ian D. Wall ◽  
Colin M. Edge ◽  
James M. Woolven ◽  
Guanglei Cui ◽  
...  
Keyword(s):  
Drug Design ◽  
Prediction Methods ◽  
Structure Based Drug Design ◽  
Site Prediction

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresdern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Drug Design ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains...

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

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.

scholarly journals SQM/COSMO Scoring Function: Reliable Quantum‐Mechanical Tool for Sampling and Ranking in Structure‐Based Drug Design

ChemPlusChem ◽  
2020 ◽  
Vol 85 (11) ◽  
pp. 2361-2361
Author(s):  
Adam Pecina ◽  
Saltuk M. Eyrilmez ◽  
Cemal Köprülüoğlu ◽  
Vijay Madhav Miriyala ◽  
Martin Lepšík ◽  
...  
Keyword(s):  
Drug Design ◽  
Scoring Function ◽  
Quantum Mechanical ◽  
Structure Based Drug Design ◽  
Mechanical Tool

A quantum mechanical approach to ligand binding — Calculation of ligand–protein binding affinities for stromelysin-1 (MMP-3) inhibitors

2009 ◽  
Vol 87 (10) ◽  
pp. 1480-1484 ◽  
Author(s):  
Jian Li ◽  
Charles. H. Reynolds
Keyword(s):  
Ligand Binding ◽  
Metal Ion ◽  
Protein Complexes ◽  
Field Method ◽  
Binding Energies ◽  
Quantum Mechanical ◽  
Binding Affinities ◽  
Bond Forming ◽  
Proton Charge ◽  
Quantum Mechanical Approach

Linear-scaling quantum mechanical method was applied to calculate binding affinities of six stromelysin-1 (MMP-3) inhibitors with two different zinc binding groups (ZBGs). The entire protein and ligand–protein complexes were calculated using PM5 Hamiltonian, which enables the treatment of metal ion coordination, bond forming/breaking, and proton/charge transfers associated with the ligand binding process by the self-consistent field method. The calculated binding energies reproduce the binding-affinity trend observed experimentally.

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