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. 2008 Oct 21;254(4):861-7.
doi: 10.1016/j.jtbi.2008.07.030. Epub 2008 Jul 29.

Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors

Veena Nukoolkarn  1 , Vannajan Sanghiran Lee, Maturos Malaisree, Ornjira Aruksakulwong, Supot Hannongbua
Affiliations

Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors

Veena Nukoolkarn et al. J Theor Biol. .

Abstract

Since the emergence of the severe acute respiratory syndrome (SARS) to date, neither an effective antiviral drug nor a vaccine against SARS is available. However, it was found that a mixture of two HIV-1 proteinase inhibitors, lopinavir and ritonavir, exhibited some signs of effectiveness against the SARS virus. To understand the fine details of the molecular interactions between these proteinase inhibitors and the SARS virus via complexation, molecular dynamics simulations were carried out for the SARS-CoV 3CL(pro) free enzyme (free SARS) and its complexes with lopinavir (SARS-LPV) and ritonavir (SARS-RTV). The results show that flap closing was clearly observed when the inhibitors bind to the active site of SARS-CoV 3CL(pro). The binding affinities of LPV and RTV to SARS-CoV 3CL(pro) do not show any significant difference. In addition, six hydrogen bonds were detected in the SARS-LPV system, while seven hydrogen bonds were found in SARS-RTV complex.

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Figures

Fig. 1
Fig. 1
Chemical formula of HIV-1 PR inhibitor, ritonavir and lopinavir, which exhibits signs of effectives against SARS.
Fig. 2
Fig. 2
Structures of (a) SARS-free enzyme, (b) SARS–lopinavir complex and (c) SARS–ritronavir complex.
Fig. 3
Fig. 3
RMSDs of SARS-CoV 3CLpro free enzyme ((a) SARS) and its complexes with lopinavir ((b) SARS–LPV) and ritonavir ((c) SARS–RTV).
Fig. 4
Fig. 4
The probability distributions of the associated interatomic distances between the distances (a) d1 and (b) d2 from the center of mass of the following residues, H41 to C145 and D48 to Q189, respectively.
Fig. 5
Fig. 5
(a) Definitions and (b) probability distributions of the torsion angles of the two catalytic residues (Tor1: CA-CB-CG-CD of H41 and TorR2: N-CA-CB-S of C145) and two amino acids at the tip of the loop (Tor3: CA-CB-CG-OD of D48 and Tor4: CB-CG-CD-CA of Q189) during 600–2000 ps of the simulations.
Fig. 6
Fig. 6
Radial distribution functions, g(r), centered on the inhibitor atoms (see Fig. 1 for definitions) to oxygen atoms of modeled water of the two complexes, SARS–LPV and SARS–RTV. The plots are classified into two categories where the central atom types for the two inhibitors are topologically (a) equivalent and (b) different.
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