Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps

Journal of Chemical Information and Modeling
Georgios LeonisManthos G Papadopoulos

Abstract

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the main targets toward AIDS therapy. We have selected the potent drug darunavir and a weak inhibitor (fullerene analog) as HIV-1 PR substrates to compare protease's conformational features upon binding. Molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and quantum-mechanical (QM) calculations indicated the importance of the stability of HIV-1 PR flaps toward effective binding: a weak inhibitor may induce flexibility to the flaps, which convert between closed and semiopen states. A water molecule in the darunavir-HIV-1 PR complex bridged the two flap tips of the protease through hydrogen bonding (HB) interactions in a stable structure, a feature that was not observed for the fullerene-HIV-1 PR complex. Additionally, despite that van der Waals interactions and nonpolar contribution to solvation favored permanent fullerene entrapment into the cavity, these interactions alone were not sufficient for effective binding; enhanced electrostatic interactions as observed in the darunavir-complex were the crucial component of the binding energy. An alternative pathway to the usual way of a ligand to access the cavity was also observed f...Continue Reading

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Citations

Nov 3, 2015·The Journal of Physical Chemistry. B·Georgios LeonisManthos G Papadopoulos
Jan 7, 2015·Journal of Molecular Graphics & Modelling·Biswa Ranjan Meher, Yixuan Wang
Jul 15, 2016·ChemMedChem·Dimitrios XanthopoulosPanagiotis Zoumpoulakis
Jun 27, 2021·Journal of Molecular Graphics & Modelling·Grigorios MegariotisDoros N Theodorou
Dec 14, 2018·ACS Infectious Diseases·Gordon J LockbaumCelia A Schiffer

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