Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol's reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times.

Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence Times / L. Mollica, I. Theret, M. Antoine, F. Perron-Sierra, Y. Charton, J.-. Fourquez, M. Wierzbicki, J.A. Boutin, G. Ferry, S. Decherchi, G. Bottegoni, P. Ducrot, A. Cavalli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 59:15(2016), pp. 7167-7176. [10.1021/acs.jmedchem.6b00632]

Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence Times

L. Mollica
Primo
;
2016

Abstract

Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol's reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times.
Crystallography, X-Ray; Diabetes Mellitus, Type 2; Glucokinase; Humans; Isoenzymes; Kinetics; Ligands; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Time Factors; Molecular Dynamics Simulation
Settore CHIM/02 - Chimica Fisica
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/926494
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