Lee vmd calculator5/11/2023 The value in these methods for advancing drug discovery is highlighted by their widespread application. These methods rigorously account for conformational dynamics and solvent interactions that are key to protein-ligand interactions and absent in coarser-grained approaches such as ligand docking. Through utilization of the Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) ( Cheatham et al., 1998 Srinivasan et al., 1998 Kollman et al., 2000 Gohlke and Case, 2004 Yang et al., 2011 Miller et al., 2012 Wang et al., 2016 Wang et al., 2018a), Linear Interaction Energy (LIE) ( Aqvist et al., 1994 Aqvist and Marelius, 2001 Aqvist et al., 2002 Gutierrez-de-Teran and Aqvist, 2012), and absolute alchemical methods ( Kirkwood, 1935 Zwanzig, 1954 Kirkwood, 1967 Bennett, 1976 Straatsma and McCammon, 1991 Gilson et al., 1997 Boresch et al., 2003 Shirts, 2012), researchers are able to evaluate biomolecular interactions that drive molecular recognition at atomic resolution and derive accurate predictions for binding free energies. Here we discuss recent developments and applications of molecular dynamics to calculate absolute binding free energies in protein-ligand binding interactions. et al., 2019 Bhati et al., 2019 Ono et al., 2020 Chen et al., 2021), structural stability ( Aldeghi et al., 2018 Jandova et al., 2018 Pourjafar-Dehkordi et al., 2019 Martin et al., 2020), and catalytic efficiency ( Xue et al., 2019 Wang K. Outside of the pharmaceutical field, binding affinity predictions find additional uses in protein engineering, and guide the rational design of mutations altering enzyme substrate/product specificity ( Kaushik et al., 2018 Li Y. Evaluation of binding free energies through virtual screening has shown promise in efficiently narrowing the chemical search space for candidate compounds and streamlining the process of lead compound optimization. Even after identification of potential ligands from initial screening assays, further refinement must be carried out to improve binding properties, ensure that off target effects are minimized, and optimize pharmacokinetic properties. This approach is costly in time and material resources ( DiMasi et al., 2016). Modern drug development requires screening over vast regions of chemical space to identify potential binders against a protein target. Here we review the varied methodology of these approaches, developments enhancing simulation efficiency and reliability, remaining challenges hindering predictive performance, and applications to problems in the fields of medicine and biochemistry. Approaches including the Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA), Linear Interaction Energy (LIE), and alchemical methods have been broadly applied to model molecular recognition for drug discovery and lead optimization. With recent advancements in computing capability and predictive accuracy, MD based virtual screening has progressed from the domain of theoretical attempts to real application in drug development. Molecular dynamics (MD) simulations enable modeling of conformational changes critical to the binding process, leading to calculation of thermodynamic quantities involved in estimation of binding affinities. The grand challenge in structure-based drug design is achieving accurate prediction of binding free energies.
0 Comments
Leave a Reply. |