Limits...
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.

Show MeSH

Related in: MedlinePlus

structure of human immunodeficiency virus-1 reverse transcriptase incomplex with DNA [Protein Data Bank code: 1T05 (Tuske et al. 2004)]. The twodomains are the p66 (coloured) and the p51 (green). The polymerase domaindisplays a highly conserved structure that resembles the shape of the humanright hand, consisting of fingers domain (magenta), palm domain (blue), thumbdomain (light blue). The p66 subunit also includes the connection domain(yellow) and ribonuclease H (RNase H) domain (orange). The polymerase activesite is located in the canter of palm, fingers and thumb subdomains. The threecatalytic aspartic acid residues (110, 185 and 186), shown in red, are locatedin the palm subdomain and bind the cofactor divalent ion (Mg2+). The RNase Hdomain is situated at the p66 C-terminus, approximately 60 Å from polymeraseactive site. The RNase H active site contains a DDE motif comprising thecarboxylates residues ASP443, GLU478, ASP498 and ASP549 that can coordinate adivalent Mg2+ ion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4660614&req=5

f01: structure of human immunodeficiency virus-1 reverse transcriptase incomplex with DNA [Protein Data Bank code: 1T05 (Tuske et al. 2004)]. The twodomains are the p66 (coloured) and the p51 (green). The polymerase domaindisplays a highly conserved structure that resembles the shape of the humanright hand, consisting of fingers domain (magenta), palm domain (blue), thumbdomain (light blue). The p66 subunit also includes the connection domain(yellow) and ribonuclease H (RNase H) domain (orange). The polymerase activesite is located in the canter of palm, fingers and thumb subdomains. The threecatalytic aspartic acid residues (110, 185 and 186), shown in red, are locatedin the palm subdomain and bind the cofactor divalent ion (Mg2+). The RNase Hdomain is situated at the p66 C-terminus, approximately 60 Å from polymeraseactive site. The RNase H active site contains a DDE motif comprising thecarboxylates residues ASP443, GLU478, ASP498 and ASP549 that can coordinate adivalent Mg2+ ion.

Mentions: The HIV-1 enzyme RT is a primary target for antiretroviral drugs. Today, 13 inhibitorsact against it, including the very first drug used in HIV treatment, the nucleoside RTinhibitor (NRTI) zidovudine (AZT) (Retrovir®) (Esposito et al. 2012). RT is the enzyme that converts thesingle-stranded RNA viral genome into a double-stranded DNA (dsDNA) provirus, which isafterwards imported into the cell nucleus to be integrated into the host chromosome withthe help of integrase (Esposito et al. 2012),another HIV enzyme. Other crucial activities of the retrotranscription process can beattributed to this highly dynamic enzyme: an endonucleolytic ribonuclease H (RNase H)activity and strand transfer (Liu et al. 2008).RT is a heterodimer (Fig. 1) composed of twosubunits of 560 and 440 amino acid (aa) residues, referred to as p66 and p51,respectively (Menendez-Arias 2013). Thesesubunits share almost the same aa sequences. However, p51 lacks the catalytic activityand the RNase H domain, performing a structural role (Kohlstaedt et al. 1992). Unlike p51, p66 has a more flexible structure andcontains the polymerase and RNase H active sites ( Kohlstaedt et al. 1992). Although, all the commercially availableRT-targeting drugs affect the polymerase activity inhibiting its function, some RNase Hinhibitors have recently been designed and studied (Tramontano & Di Santo 2010, Distinto etal. 2013) (Steitz 1999, Tuske et al. 2004).


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)

structure of human immunodeficiency virus-1 reverse transcriptase incomplex with DNA [Protein Data Bank code: 1T05 (Tuske et al. 2004)]. The twodomains are the p66 (coloured) and the p51 (green). The polymerase domaindisplays a highly conserved structure that resembles the shape of the humanright hand, consisting of fingers domain (magenta), palm domain (blue), thumbdomain (light blue). The p66 subunit also includes the connection domain(yellow) and ribonuclease H (RNase H) domain (orange). The polymerase activesite is located in the canter of palm, fingers and thumb subdomains. The threecatalytic aspartic acid residues (110, 185 and 186), shown in red, are locatedin the palm subdomain and bind the cofactor divalent ion (Mg2+). The RNase Hdomain is situated at the p66 C-terminus, approximately 60 Å from polymeraseactive site. The RNase H active site contains a DDE motif comprising thecarboxylates residues ASP443, GLU478, ASP498 and ASP549 that can coordinate adivalent Mg2+ ion.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f01: structure of human immunodeficiency virus-1 reverse transcriptase incomplex with DNA [Protein Data Bank code: 1T05 (Tuske et al. 2004)]. The twodomains are the p66 (coloured) and the p51 (green). The polymerase domaindisplays a highly conserved structure that resembles the shape of the humanright hand, consisting of fingers domain (magenta), palm domain (blue), thumbdomain (light blue). The p66 subunit also includes the connection domain(yellow) and ribonuclease H (RNase H) domain (orange). The polymerase activesite is located in the canter of palm, fingers and thumb subdomains. The threecatalytic aspartic acid residues (110, 185 and 186), shown in red, are locatedin the palm subdomain and bind the cofactor divalent ion (Mg2+). The RNase Hdomain is situated at the p66 C-terminus, approximately 60 Å from polymeraseactive site. The RNase H active site contains a DDE motif comprising thecarboxylates residues ASP443, GLU478, ASP498 and ASP549 that can coordinate adivalent Mg2+ ion.
Mentions: The HIV-1 enzyme RT is a primary target for antiretroviral drugs. Today, 13 inhibitorsact against it, including the very first drug used in HIV treatment, the nucleoside RTinhibitor (NRTI) zidovudine (AZT) (Retrovir®) (Esposito et al. 2012). RT is the enzyme that converts thesingle-stranded RNA viral genome into a double-stranded DNA (dsDNA) provirus, which isafterwards imported into the cell nucleus to be integrated into the host chromosome withthe help of integrase (Esposito et al. 2012),another HIV enzyme. Other crucial activities of the retrotranscription process can beattributed to this highly dynamic enzyme: an endonucleolytic ribonuclease H (RNase H)activity and strand transfer (Liu et al. 2008).RT is a heterodimer (Fig. 1) composed of twosubunits of 560 and 440 amino acid (aa) residues, referred to as p66 and p51,respectively (Menendez-Arias 2013). Thesesubunits share almost the same aa sequences. However, p51 lacks the catalytic activityand the RNase H domain, performing a structural role (Kohlstaedt et al. 1992). Unlike p51, p66 has a more flexible structure andcontains the polymerase and RNase H active sites ( Kohlstaedt et al. 1992). Although, all the commercially availableRT-targeting drugs affect the polymerase activity inhibiting its function, some RNase Hinhibitors have recently been designed and studied (Tramontano & Di Santo 2010, Distinto etal. 2013) (Steitz 1999, Tuske et al. 2004).

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