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Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.

Santos LH, Ferreira RS, Caffarena ER - Mem. Inst. Oswaldo Cruz (2015)

Bottom Line: Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs.However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents.Successful applications of these methodologies are also highlighted.

View Article: PubMed Central - PubMed

Affiliation: Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.

ABSTRACT
Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

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chemical structures of five approved nonnucleoside reverse transcriptaseinhibitors.
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f04: chemical structures of five approved nonnucleoside reverse transcriptaseinhibitors.

Mentions: The NNRTIs are allosteric inhibitors of DNA polymerisation. These compounds bind in anoncompetitive manner to a hydrophobic pocket (Fig.2A) located approximately 10 Å away from the polymerase active site, causingconformation changes that impair DNA synthesis (Squires2001). During the DNA synthesis, the RT fits a “closed” conformation bringingthe fingers and thumb subdomains closer to the palm one and allowing the binding ofnucleic acids. The presence of an NNRTI leads to an open conformation that restricts thethumb to a hyperextension position, which prevents the polymerisation (de Bethune 2010,Daset al. 2012). The currently approved NNRTIs are nevirapine (NVP)(Viramune®), efavirenz (Sustiva®), delavirdine (DLV)(Rescriptor®), etravirine (ETR) (Intelence®) and RPV (Fig. 4).


Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.

Santos LH, Ferreira RS, Caffarena ER - Mem. Inst. Oswaldo Cruz (2015)

chemical structures of five approved nonnucleoside reverse transcriptaseinhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660614&req=5

f04: chemical structures of five approved nonnucleoside reverse transcriptaseinhibitors.
Mentions: The NNRTIs are allosteric inhibitors of DNA polymerisation. These compounds bind in anoncompetitive manner to a hydrophobic pocket (Fig.2A) located approximately 10 Å away from the polymerase active site, causingconformation changes that impair DNA synthesis (Squires2001). During the DNA synthesis, the RT fits a “closed” conformation bringingthe fingers and thumb subdomains closer to the palm one and allowing the binding ofnucleic acids. The presence of an NNRTI leads to an open conformation that restricts thethumb to a hyperextension position, which prevents the polymerisation (de Bethune 2010,Daset al. 2012). The currently approved NNRTIs are nevirapine (NVP)(Viramune®), efavirenz (Sustiva®), delavirdine (DLV)(Rescriptor®), etravirine (ETR) (Intelence®) and RPV (Fig. 4).

Bottom Line: Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs.However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents.Successful applications of these methodologies are also highlighted.

View Article: PubMed Central - PubMed

Affiliation: Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil.

ABSTRACT
Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

Show MeSH
Related in: MedlinePlus