Special Concepts/Special Developments

Currently, Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) efavirenz and two

nucleoside analogue reverse transcriptase inhibitors are the main components used for Human
Immunodeficiency Virus (HIV) antiretroviral therapy (ART). However, the escalating cases of patients
with NNRTI drug resistance become the major global health concern nowadays as efavirenz reduces
its effectivity as first-line therapy for HIV (Rutstein et al., 2019). Effective combinations of highly active
antiretroviral therapy (HAART) are also significantly reduced (Gu et al., 2014) exposing more patients
to possible progression of their condition to Acquired Immunodeficiency syndrome (AIDS). To
address this problem, rapid development of safe and effective new drugs are needed.
Substantial number of successful research for drug design and discovery of HIV enzyme
inhibitors have been published for the past decade. Numerous in silico methods are promising for the
development of new anti-HIV drugs with three key enzymes namely: reverse transcriptase, protease,
integrase; and two key receptors namely: C-C chemokine receptor type 5 (CCR5), and C-X-C
chemokine receptor type 4 (CXCR4) (Gu et al., 2014). However, this review will only focus on the HIV
reverse transcriptase and protease inhibitions and application of computational tools for the drug
design.
Reverse Transcriptase
Reverse Transcriptase (RT) is most established target for HIV antiretroviral drug design. This
enzyme plays a vital role for the virus’ replication cycle as it facilitates replication of the RNA into a
double-stranded DNA provirus (Santos et al., 2015). The two major classes of RT inhibitors are
nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). These inhibitors have
different modes of inhibition such that NRTI stops the HIV DNA synthesis while NNRTI stops the DNA
polymerization (Dąbrowska et al., 2018). Computational tools are essential for the development of
HIV-1 RTI particularly for providing insights on the biological activities and interactions of the
compound and the target (Dąbrowska et al., 2018).
The study of Bhadoriya et al. (2015) generated pharmacophore model using the 24
compounds of diarylaniline derivatives for NNRTIs drug development. Pharmacophore features used
for this study are two hydrogen bond acceptors, one donor, and two aromatic rings. The result
showed that 12 hit molecules were successfully detected with the same 2,4-dihydropyrano [2,3-c]
pyrazole as basic nucleus, and substitutions on the 4 th position of pyran ring with aromatic group, 5 th
position with amino group, and 6th position with nitrile group.
Molecular docking is also essential for analyzing the effectiveness of newly developed anti-
viral drugs (Gu et al., 2014). The derivatives of dihydrofuro[3,4-d]pyrimidine (DHPY) in the study of
Chen et al., (2020) were examined and docked into the binding pocket of the target with the same
conformations. Based on the study, Lys101 is the main amino residue of DHPY while Tyr 181, Tyr
188, Trp229, and Phe227 also contributes to the effectiveness of the DHPY derivatives. Docking
studies also showed promising result for strong binding of (5E)-3-(2-aminoethyl)-5-benzylidene-1, 3-
thiazolidine-2,4-dione with catalytic pockets of HIV-RT such as Asp110, Asp 185, and Asp186
(Seniya et al., 2015).

Protease

Protease (PR) is also a druggable target for HIV anti-retroviral development wherein HIV PR
inhibitors hinder the formation of mature viral proteins making them non-infections (Ul-Haq et al.,
2013). Commonly, drug development focus on the binding pockets PR such as Asp25, Gly27, Ala28,
Asp29, and Gly49, and some catalytic core and C-terminal region. PR inhibitors (PI) are more prone
to drug resistance than RT inhibitors because of higher mutation chances at sites Val32, Ile50, and
Ile84 therefore, more potent drugs for PR inhibitions were being nowadays.
 The study of Nayak et al. (2018) formulated pharmacophore hypothesis from ten FDA-
approved HIV PIs using common features such as hydrogen bond acceptor (A), hydrogen bond donor
(D), hydrophobic group (H), cationic groups (P), anionic groups (N) and aromatic ring (R) via PHASE
software. Validation of the pharmacophore hypothesis was done using enrichment calculation method
with 1000 randomly selected compounds plus the active compounds. The testing showed that the
combination of three hydrogen bond acceptors (A), one hydrophobic regions (H), and one aromatic
ring (R) is the best pharmacophore hypothesis. After conducting pharmacophore-based and
structure-based screening, molecular docking, and molecular dynamics studies, lead molecules with
compound ID NCI‐524545 and ZINC12866729 have higher binding affinities to the wild type and
mutant HIV-1 PR.
References:
Chen, Y., Tian, Y., Gao, Y., Wu, F., Luo, X., Ju, X., & Liu, G. (2020). In silico Design of Novel HIV-1
NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines. Frontiers in
chemistry, 8, 164. doi: 10.3389/fchem.2020.00164
Dąbrowska, A., Pieńko, T., Taciak, P., Wiktorska, K., Chilmonczyk, Z., Mazurek, A., & Stasiulewicz,
A. (2018). Fullerene Derivatives of Nucleoside HIV Reverse Transcriptase Inhibitors—In Silico
Activity Prediction. International Journal of Molecular Sciences, 19(10),
3231. doi:10.3390/ijms19103231 
Gu, W.-G., Zhang, X., & Yuan, J.-F. (2014). Anti-HIV Drug Development Through Computational
Methods. The AAPS Journal, 16(4), 674–680. doi:10.1208/s12248-014-9604-9 
Nayak, C., Chandra, I., & Singh, S. K. (2018). An in silico pharmacological approach toward the
discovery of potent inhibitors to combat drug resistance HIV-1 protease variants. Journal of
Cellular Biochemistry. doi:10.1002/jcb.28181 
Rutstein, S.E., Chen, J.S., Nelson, J.A.E. et al. High rates of transmitted NNRTI resistance among
persons with acute HIV infection in Malawi: implications for first-line dolutegravir scale-
up. AIDS Res Ther 16, 5 (2019). doi: 10.1186/s12981-019-0220-8
Santos, L. H., Ferreira, R. S., & Caffarena, E. R. (2015). Computational drug design strategies
applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.
Memórias Do Instituto Oswaldo Cruz, 110(7), 847–864. doi:10.1590/0074-02760150239 
Seniya, C., Yadav, A., Khan, G. J., & Sah, N. K. (2015). In-silico Studies Show Potent Inhibition of
HIV-1 Reverse Transcriptase Activity by a Herbal Drug. IEEE/ACM Transactions on
Computational Biology and Bioinformatics, 12(6), 1355–1364.
Stolbov, L., Druzhilovskiy, D., Rudik, A., Filimonov, D., Poroikov, V., & Nicklaus, M. (2019). AntiHIV-
Pred: Web-resource for in silico prediction of anti-HIV/AIDS activity.
Bioinformatics. doi:10.1093/bioinformatics/btz638 
Ul-Haq, Z., Usmani, S., Shamshad, H., Mahmood, U., & Halim, S. (2013). A combined 3D-QSAR and
docking studies for the In-silico prediction of HIV-protease inhibitors. Chemistry Central
Journal, 7(1), 88. doi:10.1186/1752-153x-7-88