Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	A comparative molecular dynamics, MM-PBSA and thermodynamic integration study of saquinavir complexes with wild-type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V single mutants
Δημιουργός/Συγγραφέας:	Tzoupis H. Leonis G. [EL] Μαυρομούστακος, Θωμάς[EN] Mavromoustakos, Thomas [EL] Παπαδόπουλος, Μάνθος Γ.[EN] Papadopoulos, Manthos G.
Ημερομηνία:	2013
Γλώσσα:	Αγγλικά
ISSN:	1549-9618
DOI:	10.1021/ct301063k
Περίληψη:	A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug-protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug's binding affinity, as shown by MM-PBSA and thermodynamic integration (TI) calculations (ΔΔGTI = 0.3 kcal/mol; ΔΔGMM-PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR.
Τίτλος πηγής δημοσίευσης:	Journal of Chemical Theory and Computation
Τόμος/Κεφάλαιο:	9
Τεύχος:	3
Σελίδες:	1754-1764
Θεματική Κατηγορία:	[EL] Χημεία (Γενικά)[EN] Chemistry (General)
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2013 American Chemical Society.
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Green
Σημειώσεις:	Seventh Framework Programme, FP7: 245866
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο