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WIREs Comput Mol Sci
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Recent advances in dynamic docking for drug discovery

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Molecular docking allows the evaluation of ligand‐target complementarity. This is the crucial first step in small‐molecule drug discovery. Over the last decade, increasing computer power and more efficient molecular dynamics (MD) software have prompted the use of MD for molecular docking. The resulting dynamic docking offers major improvements by (1) taking full account of the structural flexibility of the drug‐target system and (2) allowing the computation of the free energy and kinetics associated with drug binding. Here, we examine the recent advances in dynamic docking, while also considering the challenges and limitations that this powerful approach must overcome to impact fast‐paced drug discovery.

Dynamic docking.
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Free energy profile representing the (un)binding process of a ligand (from)to the target protein. In first approximation, the thermodynamics of binding is measured by the free‐energy difference between the bond and unbound states (Δ G b), while the kinetics of (un)binding is determined by the dissociation and association rate constants, k off and k on. These are related to the free‐energy differences between minima and the transition state, Δ G off and ΔG on, respectively.
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Bottom row: average unbinding force profiles (left) and external work (right) for the undocking of the clinical candidate F14512 and etoposide from the cleavage complex, as calculated from multiple steered molecular dynamics (MD) simulations (top‐left). Top‐middle: measured relative efficiencies versus IC50 values for compounds 1–7 (top‐right). (Reprinted with permission from Ref . Copyright 2015 The Royal Society of Chemistry)
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From the crystal structure of compound R221239 (compound 3) to the modest anti‐HIV activity of the initial docking hit (compound 1) with 5 μM potency toward wild‐type (WT) human immunodeficiency virus (HIV)‐1 reverse transcriptase. This was efficiently evolved into highly potent catechol diethers, such as compound 42, which is a 55 pM non‐nucleoside inhibitor of HIV‐1 reverse transcriptase (NNRTIs) discovered using computational analyses guided by free‐energy perturbation (FEP) results. Source: De Vivo et al.
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Software > Molecular Modeling
Simulation Methods > Molecular Mechanics
Structure and Mechanism > Computational Biochemistry and Biophysics

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