Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model.

Journal of Chemical Information and Modeling
Debananda DasHiroaki Mitsuya

Abstract

Reliable and robust prediction of the binding affinity for drug molecules continues to be a daunting challenge. We simulated the binding interactions and free energy of binding of nine protease inhibitors (PIs) with wild-type and various mutant proteases by performing GBSA simulations in which each PI's partial charge was determined by quantum mechanics (QM) and the partial charge accounts for the polarization induced by the protease environment. We employed a hybrid solvation model that retains selected explicit water molecules in the protein with surface-generalized Born (SGB) implicit solvent. We examined the correlation of the free energy with the antiviral potency of PIs with regard to amino acid substitutions in protease. The GBSA free energy thus simulated showed strong correlations (r > 0.75) with antiviral IC(50) values of PIs when amino acid substitutions were present in the protease active site. We also simulated the binding free energy of PIs with P2-bis-tetrahydrofuranylurethane (bis-THF) or related cores, utilizing a bis-THF-containing protease crystal structure as a template. The free energy showed a strong correlation (r = 0.93) with experimentally determined anti-HIV-1 potency. The present data suggest that the...Continue Reading

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Citations

Nov 23, 2013·Applied Biochemistry and Biotechnology·Chandrabose SelvarajSanjeev Kumar Singh
Jan 26, 2010·Journal of Chemical Information and Modeling·Sourav DasCurt M Breneman
May 30, 2014·Journal of Molecular Modeling·Paulius MikulskisUlf Ryde
Jun 17, 2016·Journal of Receptor and Signal Transduction Research·Pradeep NatarajanUmamaheswari Amineni
Nov 19, 2014·Journal of Receptor and Signal Transduction Research·Venkatesan Suryanarayanan, Sanjeev Kumar Singh
Sep 22, 2012·Journal of Molecular Recognition : JMR·Sunil Kumar TripathiChandrabose Selvaraj
Mar 5, 2014·Journal of Molecular Recognition : JMR·Jeyachandran SivakamavalliBaskaralingam Vaseeharan
Apr 4, 2014·Journal of Receptor and Signal Transduction Research·Chandrabose SelvarajSanjeev Kumar Singh
Jul 24, 2014·Journal of Receptor and Signal Transduction Research·Periyasamy Vijayalakshmi, Pitchai Daisy
Apr 9, 2016·Biochemistry Research International·R BalajeeP Gunasekaran
Jun 4, 2013·Journal of Theoretical Biology·Sunil Kumar TripathiSanjeev Kumar Singh
Jul 23, 2013·Journal of Biomolecular Structure & Dynamics·Chandrabose Selvaraj, Sanjeev Kumar Singh
Jun 24, 2016·Journal of Biomolecular Structure & Dynamics·V SivaramakrishnanBhadrapura Lakkappa Dhananjaya
Aug 5, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Panagiota-Yiolanda StergiouEmmanuel M Papamichael
Feb 26, 2016·Journal of Receptor and Signal Transduction Research·Sudheer Kumar KatariAmineni Umamaheswari
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Jul 10, 2019·Journal of Receptor and Signal Transduction Research·K LangeswaranK R Dhurgadevi
Apr 9, 2020·Journal of Biomolecular Structure & Dynamics·Shafi MahmudMd Abu Saleh
Jan 1, 2021·Journal of Biomolecular Structure & Dynamics·Abha MishraAmit Singh
Jul 3, 2021·International Journal of Molecular Sciences·Satyavani KaliamurthiGilles H Peslherbe
Aug 19, 2021·Journal of Biomolecular Structure & Dynamics·Sudheer Kumar KatariAmineni Umamaheswari

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