MD studies Everolimus were used to provide a new insight into the mechanism of interactions of HIV 1 IN and vDNA and the inhibition mechanism of RAL. The results from MD simulations showed that the inter hydrogen bonds and electrostatic contributions at the HIV 1 IN and vDNA interface play a key role to guide HIV 1 IN and vDNA during the recognition process. Furthermore, we studied the critical conformational changes with RAL free and bound states. It is demonstrated from the MD simulation that RAL binds to a pocket in the HIV 1 IN– vDNA complex through interactions with Mg2þ ions and the vDNA end, and forces the 30 OH of the terminal A17 nucleotide away from the HIV 1 IN active site, which can prevent the vDNA strand transfer.
The proposed novel inhibition mechanism of RAL against HIV 1 IN–vDNA complex provides a new chance and a reliable platform for the structure based drug design and discovery targeting integration process of HIV mGluR 1.Lersivirine is a new nonnucleoside reverse transcriptase inhibitor currently being developed as a treatment for human immunodeficiency virus type 1 infection. Lersivirine shows potent activity against wild type and clinically relevant drugresistant strains. Previous studies have demonstrated that lersivirine is metabolized by glucuronidation via UGT2B7 and by cytochrome P450 3A4 . Lersivirine is also a weak inducer of the CYP3A4 enzyme. Therefore, coadministered lersivirine could potentially affect the pharmacokinetics of maraviroc, a CCR5 antagonist metabolized by CYP3A4, and raltegravir, an integrase inhibitor metabolized by glucuronidation.
Two open label studies assessed the pharmacokinetics of raltegravir and of maraviroc when they were coadministered anthropology with lersivirine and the pharmacokinetics of lersivirine when it was coadministered with raltegravir. Minor, clinically nonsignificant effects on the pharmacokinetics of raltegravir coadministered with lersivirine were observed at steady state for raltegravir, with estimated mean changes of15%,29%, and 25% in the area under the concentration time profile from time zero to the end of the dosing interval , maximum plasma concentration , and concentration observed 12 h postdose , respectively. There were no clinically relevant effects of steady state raltegravir on lersivirine AUCtau, Cmax, or concentration observed 24 h postdose .
Coadministration of lersivirine at steady state with maraviroc resulted in no clinically relevant effects on maraviroc AUCtau, Cmax, or C12 . Lersivirine appeared to be generally well tolerated in these studies and appears to be suitable for coadministration with raltegravir or maraviroc without the need for dose modification. Human immunodeficiency virus infected patients are frequently prescribed combination antiretroviral therapy regimens, which typically consist of at least three different drugs from at least two different classes. Currently approved antiretroviral drugs lude nucleoside reverse transcriptase inhibitors , nonnucleoside reverse transcriptase inhibitors , protease inhibitors, integrase strand transfer inhibitors , entry inhibitors, and chemokine receptor antagonists . The emergence of drug resistant virus in patients treated with antiretroviral therapy, and the reasing prevalence of resistance mutations in transmitted.