Rohit Arora

Structural Flexibility of Raltegravir and Dynamics of HIV-1 Integrase

 

​The HIV-1 Integrase is an essential retroviral enzyme that covalently binds both ends of linear viral DNA and inserts them into a cellular chromosome. The functions of this enzyme are based on the existence of specific attractive interactions between partner molecules or cofactors ‒ viral DNA and Mg2+ cations. We sought to identify and use such interactions by structure-based in silico methods, to design and optimize the competitive and specific modulator of such functional interactions. 

We utilised the available structural information related to the retroviral integrase. We used this data to generate biologically relevant HIV-1 targets ‒ the unbound IN, the viral DNA (vDNA) and the IN/vDNA complex ‒ which represent with a certain level of reliability, two different enzymatic states of the HIV-1 over the retroviral integration process.

We also studied the structural characterstics of Raltegravir (or Isentress; the only FDA approved Integrase inhibitor). Like other anti-retrovirals, Raltegravir develops/indces resistance effects. We characterised the binding of Raltegravir , a very flexible molecule displaying the E/Z isomerism, to the active site of its HIV-1 targets which mimic the integrase states before and after the 3’-processing. The docked conformations represent a spectrum of possible conformational/configurational states. The best docking scores and poses confirm that the generated model representing the IN/vDNA complex is the biologically relevant target of Raltegravir - the strand transfer inhibitor. This finding is consistent with well-documented and commonly accepted inhibition mechanism of Raltegravir, based on integral biological, biochemical and structural data.RAL docking onto the IN•vDNA complex systematically generated the RAL chelated to Mg2+cations at the active site by the pharmacophore oxygen atoms.

The identification of IN residues specifically interacting with RAL is likely a very difficult task and the exact modes of binding of this inhibitor remain a matter of debate. Most probably the flexible nature of RAL results in different conformations and the mode of binding may differ in terms of the interacting residues of the target, which trigger the alternative resistance phenomenon.

 

This work was performed at ENS Cachan during my PhD thesis, which led to a successful defense. Please see the publication list for more information on this work

 

 

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