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Aromatic interaction profile to understand the molecular basis of raltegravir resistance

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Abstract

Integrase (IN) is the enzyme of human immunodeficiency virus (HIV) which inserts the viral DNA (vDNA) into the host genome for successful viral replication leading to the infection. However, the chemical basis of HIV IN catalysis is speculative due to lack of complete co-crystal structure. Using the recently published prototype foamy virus IN crystal structure, we developed a model structure of HIV IN showing interaction of vDNA, the metal (Mg2+) cofactor, and raltegravir (RLT) in the active site. Molecular docking and dynamics simulations studies showed that RLT uses it core central ring with diketo motif for Mg2+ chelation and bridge interaction with DDE motif. The triple arene interactions mediated by RLT with neighboring molecular motifs (Y143, cytosine, and adenine) is maintained during long simulation in wild type (WT). The fluorobenzyl and oxadiazole moieties of RLT forms aromatic stacking with cytosine base (head stacking) aromatic side chain of Y143 (tail stacking), respectively, while central ring further establishes aromatic stacking with distorted adenine base of vDNA (central stacking). The novel triple stacking systems were further explored to understand the molecular basis of drug resistance by molecular simulation. The in silico mutation (N155H, Q148H, and Q148H + G140S) and simulation studies elucidated the structural mechanism of resistance to RLT. The simulation studies provided the molecular basis for interdependency observed for the primary and secondary (Q148H and G140S) mutations and also explained the mechanism of viral fitness regain. Our study reveals that triple stacking and its consequence in terms of VdW energetic profile acts as a critical point to understand the drug-resistance. Here, we demonstrate that the root mean square deviation of centroid system (aromatic stacking) can be used as a major determinant of RLT binding toward the fold resistance. This is first kind of report, which discloses a strategy to explore the molecular level of drug resistance profile using aromatic interactions.

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Abbreviations

HIV-1:

Human immunodeficiency virus type 1

PFV-1:

Prototype foamy virus type 1

RLT:

Raltegravir

ARVs:

Antiretroviral drugs

IN:

Integrase

RT:

Reverse transcriptase

INSTI:

IN strand transfer inhibitor

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Acknowledgments

Authors thanks Department of Biotechnology, Government of India for financial support (BT/PR14237/MED/29/196/2010). TB gratefully acknowledges the award of Junior Research Fellowship from Department of Science and Technology, Government of India (DST Grant No: SR/FT/CS-001/2009). AK thanks the computational facility at CRS4 (Polaris), Pula, Italy.

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Authors and Affiliations

  1. Department of Applied Chemistry, Birla Institute of Technology, Mesra, Ranchi, 835215, Jharkhand, India

    Tuniki Balaraju, Chandralata Bal & Ashoke Sharon

  2. Bioengineering Group, CRS4, Science and Technology Park Polaris, Piscina Manna, 09010, Pula, CA, Italy

    Amit Kumar

  3. ICMR Virus Unit, ID & BG Hospital, General Block 4, 57 Dr Suresh C Banerjee Road, Beliaghata, 700010, Kolkata, India

    Debprasad Chattopadhyay

  4. College of Pharmacy, The Ohio State University, 634 Riffe Building 496 W. 12th Ave., Columbus, OH, 43210, USA

    Nivedita Jena

  5. Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA

    Naresh Chandra Bal

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  1. Tuniki Balaraju
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  2. Amit Kumar
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  3. Chandralata Bal
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Correspondence to Ashoke Sharon.

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Balaraju, T., Kumar, A., Bal, C. et al. Aromatic interaction profile to understand the molecular basis of raltegravir resistance. Struct Chem 24, 1499–1512 (2013). https://doi.org/10.1007/s11224-012-0181-1

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