Letters in Drug Design and Discovery, 10, 706-712

Bifunctional anti-HIV/TB inhibitors: perspective from in-silico design and molecular dynamics simulations.

Lauren Blakea and Mahmoud E. S. Solimana*

Link to the article: http://www.ingentaconnect.com/content/ben/lddd/2013/00000010/00000008/art00006


A Hybrid pharmacophore and structure-based drug design approach, aided by binding mode analysis, molecular dynamics simulations and per-residue energy contribution calculations, was used to design five novel structural scaffolds as potential bifunctional anti-HIV/TB inhibitors.  Binding free energy calculations demonstrated that the proposed compounds exhibited better binding affinities towards HIV PR and BlaC enzymes when compared to prototype drugs, darunavir and meropenem, respectively.  The lead design strategy presented in this work could serve as a useful tool for developing bifunctional inhibitors against wide range of biological targets.




Globally, the risk of developing tuberculosis (TB) is estimated to be between 20-37 times greater in people living with HIV than among those without HIV infection. In 2010, there were 8.8 million new cases of TB, of which 1.1 million were among people living with HIV [1].  South Africa alone accounted for 17% (about 5.5 million people) of the global burden of HIV infection in 2007 [2].

Recently, a WHO-led meta-analysis revealed that antiretroviral therapy (ART) reduces the risk of tuberculosis (TB) infection by 65% in people living with HIV [3].

Keeping all aforementioned facts in mind, we envisage that a dual acting anti-HIV/TB therapy using a single drug could result in synergetic targets inhibitory activity, lower toxicity, simplified dosing, and improved patient adherence, consequently, reducing the possibility of drug resistance.

We anticipated that the use of two FDA-approved anti HIV and anti-TB drugs, Darunavir and meropenem, as prototypes in the design of novel inhibitors that combine the pharmacophoric features of both drugs could lead to potential bifunctional anti HIV/TB leads.

MS-fig1Figure 1. The design of dual acting HIV PR/BlaC inhibitors is based on the use combined pharmacophoric features of two FDA-approved anti-HIV and anti-TB  drugs, Darunavir and meropenem, respectively.


Exploiting the structural information of known HIV PR and BlaC inhibitors, darunavir and meropenem, respectively, and understanding their binding mechanisms to the targets, five novel leads were proposed as potential bifunctional HIVPR/BlaC inhibitors.   Via integrated computational approaches involving “loop docking”, molecular dynamics simulations and per-residue interactions calculations, the proposed structures were found to exhibit better binding affinities when compared to the prototype drugs.  Inclusion of bis-tetrahydrofuranyl moiety was found to enhance the binding affinity towards both RT and BlaC.

MS-fig2Figure 2. Compound 3 and 4 in complex with BlaC and HIV PR, a and b, respectively, showing the hydrogen bonding and electrostatic interactions with enzymes active site.


This study could serve as an initial point towards the design of potential bifunctional anti-HIV/TB drugs.  The in-silico concept of designing dual inhibitors introduced in this study could be useful in the process of drug design and development.



Authors thank the Center of High Performance Computing (www.chpc.ac.za) in Cape Town for computational resources and the School of Health Sciences, UKZN, for financial support.



[1]        Tuberculosis and HIV, avaialble at http://www.who.int/hiv/topics/tb/en/ (Date accessed 3 February 2013).

[2]        Salim, A. K. S.; Gavin, J. C.; Quarraisha, A. K.Stephen, D. L. HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response, The Lancet, 2009, 374, 921 – 933.

[3]        Reduction of tuberculosis infection risk in people living with HIV through antiretroviral therapy. available at http://www.who.int/hiv/topics/tb/plosarticle/en/index.html (Date accessed 5 Feburary 2013).


Dr Mahmoud E. Soliman (PhD)

B.Pharm, M.Pharm, MPhil/PhD (Bath, UK)

Senior Lecturer – Pharmaceutical Chemistry

School of Health Science

Westville Campus

Private Bag X54001

Durban 4000

South Africa

Tel: +27 (0) 312607413

Fax: +27 (0) 312607413

Website: http://soliman.ukzn.ac.za


Editor in Chief

Journal of Organic & Biomolecular Simulations “JOBS”

Science Publications – USA



Journal of Pharmaceutical chemistry

Academic Visitor

University of Bath – United Kingdom

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann