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Drug design strategies using non nucleoside reverse transcriptase inhibitors

(NNRTI): current challenges and future perspectives

Article · January 2014

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 Journal of Biological and Review article
Chemical Sciences (JBCS) Sharma et al. (2014) vol.1, no. 1, 1-12

Drug design strategies using non nucleoside reverse transcriptase inhibitors

(NNRTI): current challenges and future perspectives

Ravi Sharma1, Gaurav Kumar2, Preeti Saini3, Hardeep Singh Tuli 4*, Shivani Sood4

1
Department of Biotechnology, Mata Gujri Collage, Fatehgarh Sahib, India
2
Department of Biochemistry, Kurukshetra University, Kurukshetra-136119, India
3
Department of Microbiology, PAU, Ludhiana-141004, India
4
Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala-133207

*Correspondence at hardeep.biotech@gmail.com
Received: September 13, 2014; Accepted: November 06, 2014

Abstract: The emerging drug resistance towards anti-HIV compounds attracted the attention of
scientific community. Development of potent anti-HIV therapy using non-nucleoside reverse
transcriptase inhibitors (NNRTIs) known to be a promising strategy. Although NNRTIs has
great importance in HIV-1 treatment and prevention but their mechanism of action has not yet
been studied in detail. The present review discusses cellular interactions of HIV-1 followed by
the FDA approved anti-HIV-1 chemotherapy. The review highlights the importance of NNRTIs
and their mechanism of action in HIV-1 treatment. Also the current challenges and future
prospective of NNRTIs to prevent HIV-1infection are well addressed so as to propose the
development of novel therapeutic strategies for its treatment.
Key words: HIV-1; non-nucleoside reverse transcriptase inhibitors; mechanism; QSAR;
Computer-aided drug design

Introduction
Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease caused by infection with the
human immunodeficiency virus (HIV) [1, 2]. In recent years AIDS become a serious global
threat to human health and life. HIV harms body’s immune system (T-cells) and hence gradually
destroys the body’s ability to fight against various infections as well as certain types of cancer.

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Reverse transcriptase (RT) an enzyme that catalyzes the transcription of single stranded viral
genomic DNA to double stranded DNA, has been a prominent target in the discovery and
development of therapies for HIV treatment. The first anti-HIV agent approved for clinical use
was a nucleoside reverse transcriptase inhibitor (NRTI) [3]. However, HIV strains with reduced
sensitivity toward NRTI have been isolated from patients receiving prolonged therapy. Further
non-nucleoside HIV-1 RT inhibitors (NNRTI’s) were recognized as specific inhibitors of HIV-1.
These compounds induce a conformational change in the three-dimensional structure of the RT
resulted in loss of activity [4]. NNRTIs binding are found to be virus-strain-specific and have
been used in combination with two or three other anti-HIV drugs in Highly Active Antiretroviral
Therapy (HAART).
However, in spite of the remarkable potency of NNRTIs against HIV-1, the rapid clinical
development of NNRTIs is hindered due to more susceptibility toward resistance than any other
classes of antiretroviral drugs. As single-amino-acid change in NNRTI-binding pocket can result
in complete loss of drug activity [5]. Consequently, there is an urgent need to draw attention of
scientific community for the development of new RT inhibitors with an alternative mechanism of
action. The present review focused on the approaches targeted for HIV-1 therapy with special
reference to NNRTI.
Cellular interaction of HIV
Human CD4+ T lymphocytes, macrophages, microglial, dendritic and Langerhans cells are
considered as potential targets for HIV-1 infection. Endogenous CD4 molecule a 55-KDa protein
member of the IgG super family, is a cell surface receptor expressed on helper T lymphocytes,
monocytes, B-lymphocytes and several other cells. The replication cycle of HIV begins with the
high-affinity binding of the gp120 protein on the host cell surface [6]. This gp120-CD4 complex
interacts with a coreceptor on the cell surface and mediates to complete virus entry into the host
cell. The whole process is assumed to be accomplished with the help of a cytoplasmic peptidyl-
prolyl cis-trans isomerase cyclophilin A (hCyp-18) and appears to be essential for infection by
most HIV-1 strains [7, 8]. The exact role of cyclophilins in HIV-1 infection yet to be fully
explored but studies indicated that virion associated with CyPA may be involved in an early
interaction.

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Reverse transcriptase (RT)

HIV-1 RT was discovered in the year 1970 by two independent groups, a Baltimore group and
the Termin and Mizutani group. HIV-1RT, a heterodimer contains subunits of 66 kDa (p66) and
51 kDa (p51). p66 subunit contains two domains, the N-terminal polymerase domain of about
440 residues and the C-terminal RNase H domain with 120 residues. p51 subunit is processed by
proteolytic cleavage of p66 and corresponds to the polymerase domain of the p66 subunit.
Portions of both p51 and the polymerase domain of p66 can be described as a "right hand" which
contains three sub domains: Fingers, palm, and thumb. The connection sub domain connects the
hand of the polymerase domain and RNAse H domain of p66. The connection sub domains and
the palm sub domains comprise of three-stranded β-sheets with -helices on one side whereas
the thumb sub domains include three -helices. There have been 245 structures of HIV-1 RT
deposited in the Protein Database so far.

Fig. 1: Illustrations of cellular interactions of HIV-1 with Human CD4+ T lymphocytes

Anti-HIV chemotherapy
The treatment of the acquired immunodeficiency syndrome (AIDS) is the most challenging
problem worldwide for medical scientist. Anti-HIV compounds that have been approved by FDA
for clinical use in the treatment of AIDS are summarized in Table-1. These compounds fall into
six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine,

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zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase

inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs:
nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir,
indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir);
cell entry inhibitors [fusion inhibitors (FIs: enfuvirtide) and co-receptor inhibitors (CRIs:
maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in
drug combination regimens (Table 1) to achieve the highest possible benefit, tolerability and
compliance and to diminish the risk of resistance development.

Fig. 3: mechanism of action of NNRTI’s

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Table 1. Anti-HIV compounds approved by FDA in the treatment of AIDS

Nucleoside Generic name Brand Manufacturer FDA

Reverse name approval
Transcriptase Abacavir Ziagen Viiv Healthcare 1998
Inhibitors Didanosine Videx Bristol-Myers Squibb 1991
(NRTIs) Videx EC 2000
Emtricitabine Emtriva Gilead Sciences 2003
Lamivudine Epivir Viiv Healthcare 1995
Zerit Zerit Bristol-Myers Squibb 1994

Tenofovir Disoproxil Viread Gilead Sciences 2001

Fumarate
Zidovudine Retrovir Viiv Healthcare 1987
Non-Nucleoside Delavirdine Rescriptor Viiv Healthcare 1997
Reverse
Transcriptase Efavirenz Sustiva Bristol-Myers Squibb 1998
Inhibitors Etravirine Intelence Janssen 2008
(NNRTIs) Pharmaceuticals, Inc.
Nevirapine Viramune Boehringer 1996
Viramune Ingelheim 2011
Rilpivirine Edurant Janssen Pharmaceuticals, 2011
Inc.
Protease Atazanavir Reyataz Bristol-Myers Squibb 2003
Inhibitors (PIS) Darunavir Prezista Janssen Pharmaceuticals, 2006
Inc.
Fosamprenavir Lexiva Viiv Healthcare 2003
Indinavir Crixivan Merck & Co., Inc 1996
Nelfinavir Viracept Agouron 1997
Ritonavir Norvir Abbvie Inc. 1996
Saquinavir Invirase Hoffmann-La 1995
Tipranavir Aptivus Boehringer Ingelheim 2005
Fusion Inhibitors Enfuvirtide Fuzeon Hoffmann-La Roche 2003
Entry Inhibitors Maraviroc Selzentry Viiv Healthcare 2007
Integrase Dolutegravir Tivicay Viiv Healthcare 2013
Inhibitors Raltegravir Isentress Merck & Co., Inc. 2007
Combination abacavir and lamivudine Epzicom ViiV Healthcare 2004
HIV Medicines
abacavir, dolutegravir, Triumeq ViiV Healthcare 2014
and
lamivudine
abacavir, lamivudine, Trizivir ViiV Healthcare 2000
and
zidovudine
efavirenz, emtricitabine, Atripla Bristol-Myers 2006
and Squibb
tenofovir disoproxil Gilead Sciences

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fumarate
elvitegravir, cobicistat†, Stribild Gilead Sciences 2012
emtricitabine, and
tenofovir disoproxil
fumarate
emtricitabine, rilpivirine, Stribild Gilead Sciences 2011
and tenofovir disoproxil
fumarate
emtricitabine and Truvada Gilead Sciences 2004
tenofovir
disoproxil fumarate
lamivudine and Combivir ViiV Healthcare 1997
zidovudine
lopinavir and ritonavir Kaletra AbbVie Inc. 2000

Mechanism of NNRTIs
Non-nucleoside HIV-1 RT inhibitors (NNRTI’s) were the first to be recognized as specific
inhibitors of HIV-1. These have been identified by iterative screening using purified viral
enzyme [9] and included a variety of chemical substrates which binds to hydrophobic pocket of
p66 subunit of HIV-1 reverse transcriptase. The non nucleoside reverse transcriptase binding
pocket (NNRTBP) has been found to a close distance from the active catalytic site of HIV-1 RT
and considered as non essential for enzyme function. NNRTIs bind noncompetitively at
NNRTBP and induce a conformational change in the three-dimensional (3D) structure of enzyme
results in loss of enzyme activity [4]. As a result of NNRTI binding, rate of dNTPs incorporation
into synthesizing DNA strand slower down.
Drug Design
Computational methods have developed into very useful tools in facilitating new drug discovery
[10]. By the use of computational methods, it becomes possible to estimate the biological activity
of the candidate molecules even before experimental trials. These methods are simple and non-
expensive and expedite to design molecules with desirable biological activity [11]. Quantitative
structure-activity relationship (QSAR) and docking procedure are two mostly used
computational methods in drug design.
In a study, hologram quantitative structure-activity relationship (HQSAR) was applied to three
different data sets, such as 70 TIBO, 101 HEPT and 125 dipyridodiazepinone derivatives with

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the inhibitory effect on enzyme activity [12]. Similarly Zhou and Madura (2004) docked 50
TIBO inhibitors and demonstrated that combination of ligand-based and receptor-based
modeling as a powerful approach to build 3D-QSAR models [13]. Another group of researcher
studied quantitative structure-activity relationship (QSAR) analysis for a set of 82 TIBO
(4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk] [1,4]benzodiazepin-2(1H)-ones) derivatives
using three-layered neural network [14]. Medina-Franco et al. (2004) applied a set of pyridinone
derivatives to study the interactions between pyridinone derivatives and binding pocket of non-
nucleoside reverse transcriptase inhibitor using CoMFA, CoMSIA and docking experimentation
[15]. Also researchers explained the viral resistance to pyridinone derivatives upon mutation of
amino acids Tyr181 and Tyr188. In their other study they designed 44 non-nucleoside HIV-1
reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative [16] and found pyrazolo
[3,4-d] pyrimidine and phenothiazine as promising novel compounds for NNRTIs. Another class
of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors includes indolyl aryl sulfones
(IASs) have been studied against wild type and resistant strains (Y181C, the double mutant
K103N-Y181C, and the K103R-V179D-P225H strain). A predictive 3-D QSAR models have
been designed using receptor-based alignment of IASs into the non-nucleoside binding site
(NNBS) of RT [17]. Similarly Duchowicz et al. (2006) studied 154 non-nucleoside reverse
transcriptase inhibitors (NNRTI) of the wild-type HIV-1 virus which considered as the second
generation analogues of Efavirenz [18]. A series of 74 dihydroalkoxybenzyloxopyrimidines
(DABOs) have been studied by comparative molecular field analysis (CoMFA) in order to
design more potent DABO analogues as anti-HIV/AIDS agents [19]. Hu et al. 2009 carried out
molecular modeling of a series of non-nucleoside reverse transcriptase inhibitors (2-amino-6-
arylsulfonylbenzonitriles and their thio and sulfinyl congeners) using comparative molecular
field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)
approaches [20]. Study revealed, 2-amino-6-arylsulfonylbenzonitriles with bulky and
hydrophobic groups in 3- and 5-position of the B ring showed significant inhibitory activity.
Group of researcher investigated symmetric formimidoester disulfides (DSs) as a new class of
potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors using computational strategy
[21]. Liu et al. (2010) discovered and studied a series of 4,6-diamino-1,3,5-triazin-2-ol based

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NNRTIs compounds using SAR approaches [22]. Samuelea et al. (2010) reported Novel
benzimidazol-2-one non-nucleoside reverse transcriptase inhibitors (NNRTIs) through rational
structure-based molecular modeling and docking approaches [23]. Elena et al. (2011) identified
3,4,5-Trisubstituted-1,2,4-4 H-triazoles (TTs) as a new class of potent non-nucleoside HIV-1
reverse transcriptase (RT) inhibitors [24]. Furthermore they studied 1,3,4,5-tetrasubstituted-
pyrazoles (TPs) as NNRTIs by computational strategy based molecular docking approaches
[25]. Group of researchers conducted a study on a series of 119 NNRTIs, including 1-(2-
hydroxyethoxymethyl)-6-(phenylthio) thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine
(DABO) derivatives using computational approaches [26]. Recently a series of 107 1-[(2-
hydroxyethoxy)-methyl]-6-(phenylthio) thymine (HEPT) as a non-nucleoside reverse
transcriptase inhibitor (NNRTI) has been deliberated [27].
Current challenges
NNRTIs are more susceptible to high-level drug resistance than other classes of antiretroviral
drugs because of a single-amino-acid change in the NNRTI-binding pocket. Due to this reason
the clinical development of NNRTIs is hindered [28]. The amino acids with which the NNRTIs
interact within the NNRTI-binding pocket may be prone to mutate, and this has proven to be the
case for, among others. Most of the NNRTI resistance mutations are found in and around the
NNIBP. K103N and Y181C are the most frequently observed resistance mutations in patients
treated with the approved NNRTIs. When, compared with the ‘older’ NNRTIs (e.g. nevirapine),
the ‘newer’ NNRTIs such as Etravirine and Rilpivirine first described by Janssen, et al. in 2005,
have been found to retain sufficient activity against the K103N and Y181C reverse transcriptase
(RT) mutants [29]. Other NNRTI resistance mutations that are observed in patients include
L100I, K101E, V106A, V179D, Y188L, G190A, and P236L; these NNRTI resistance mutations
can occur singly, or in combinations. The most promising third generation NNRTIs are proven to
be more effective against HIV strains that carry most common single and double mutations;
however, viral strains carrying multiple NNRTI-resistance mutations can exhibit significant
levels of drug resistance. Currently there are four NNRTI drugs Nevirapine, Delavirdine (first
generation), Efavirenz (second generation), and Etravirine (third generation)) that are approved
for treating HIV-1 infections while several other potent NNRTIs that inhibit HIV-1 at nanomolar

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concentrations (EC50) are in clinical trials. In recent years, extensive crystallographic, molecular
modeling and biochemical studies have contributed towards understanding NNRTI drug
resistance and the development of better NNRTIs with improved drug profile.
Conclusion and future perspectives
Reverse transcriptase is known as a key enzyme needed for HIV-1 replication. The present
review gives a brief summary of the last decade investigations for designing anti-HIV agents
(NNRTIs) using computer-aided approaches. It has been found that NNRTIs could play an
important role to design a promising therapy for HIV treatment. Also the development of QSAR
based drug designing models with a novel mechanism of actions could improve the pace of new
anti-HIV drug inventions. It is essential to study and Understanding the molecular mechanism of
NNRTI inhibition to overcome the drug-resistance mutations in RT. Further scientific
communities should be more focused on highly specific NNRTI inhibitors with low toxicities
and minimal side effects.
Conflict of Interest
There is no potential conflict of interest with reference to the current manuscript. All the authors
have read the manuscript and agreed to submit the same for publication.
Acknowledgement
The authors would like to acknowledge Mata Gujri Collage (Fatehgarh Sahib) for providing the
requisite facilities to carry out this work.
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