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Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

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Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches
Xanthopoulos D.
Παπαδόπουλος, Μάνθος Γ.
Kritsi E.
Leonis G.
Ζουμπουλάκης, Παναγιώτης
Supuran C.T.
Άρθρο σε επιστημονικό περιοδικό
2016
A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson–Boltzmann surface area free-energy calculations for the five ligand–HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50′), as well as interactions with residues of the active site (Asp25/25′/29/29′/30/30′). Binding-energy calculations for the three most promising compounds yielded values between −5 and −10 kcal mol−1and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding-energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit-to-lead optimization toward improved anti-HIV drugs.
Φαρμακευτική χημεία (EL)
Pharmaceutical chemistry (EN)
inhibitors (EN)
drug discovery (EN)
HIV (EN)
molecular modeling (EN)
proteases (EN)
English
John Wiley and Sons Ltd
ChemMedChem
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim (EN)
National Hellenic Research Foundation (NHRF)
Helios - Repository of the National Hellenic Research Foundation (NHRF)



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