|dc.description.abstract||HIV/AIDS still remains to be a challenging epidemic infecting millions of individuals
worldwide. The morbidity and mortality rates of HIV-infected patients has been well
documented over the years. Despite on-going HIV/AIDS research and access to antiretroviral
therapy, to date still no cure exists for this deliberating disease.
In recent years, computational approaches have emerged as close counterparts to experiments in
modern drug discovery process and in understanding complex biological phenomena. An array
of in-silico computational techniques were implemented ranging from molecular dynamic (MD)
simulations, de-novo design, hybrid structure-based and pharmacophore-based virtual screening,
quantitative structure-activity relationship (QSAR), homology modeling, principle component
analysis (PCA), residue interaction network analysis (RIN), substrate envelope analysis (SEA),
to molecular mechanics and quantum mechanics.
The first report (Chapter 4), demonstrated a unique strategy for developing dual acting inhibitors
against HIV-1 protease (PR) and reverse transcriptase (RT). The designed targets exhibited
binding affinities and dual inhibiting activity comparable to, and in some cases better than,
known active reference drugs.
The second study (Chapter 5), reported the activity of flexible hydroquinone-based compounds
as non-nucleoside reverse transcriptase inhibitors (NNRTIs), as proposed by Bruccoleri, where
no experimental or computational work supported his proposal. Results concluded that the novel
flexible hydroquinone-based compounds showed improved binding affinity as compared to
FDA-approved prototype drugs and more specifically potent potential mutant-resistant NNRT
The third report (Chapter 6), explored the activity of novel CCR5 antagonists as potential HIV-
1 entry inhibitors. Ten scaffolds were identified as novel CCR5 antagonists or potential HIV-1
entry inhibitors. Furthermore, from the generated atom-based 3D-QSAR model, all of the
parameters showed certain reliability and feasible predictability to help us design new and high
selectivity CCR5 inhibitors.
The fourth study (Chapter 7), explored the atomistic basis of why the M184I single mutation
renders complete resistance of HIV-1 RT to lamivudine. Multiple molecular dynamics
simulations, binding free energy calculations, principle component analysis (PCA) and residue
interaction network (RIN) analyses adequately clarified the effect of the M184I mutation on drug
resistance to lamvudine. Results presented in this study verified that M184I mutation decreased
drug binding affinity, distorted ligand optimum orientation in RT active site and affected the
overall protein conformational landscape. The results also provided some potential clues for
further design of novel inhibitors that are less susceptible to drug resistance.
In the fifth study (Chapter 8), we identified potential HIV-Nef inhibitors by exploiting the
structural features of B9 using an integrated computational tools framework. The top identified
hit compounds demonstrated comparatively better binding affinities and relatable binding modes
compared to the prototype antagonist, B9. Top identified hits were proposed as new potential
novel leads targeting HIV-Nef with a detailed analysis of their respective binding modes.
The sixth report (Chapter 9), aimed to reveal the dimer packing and unpacking phenomena of
HIV-Nef in its apo and inhibitor bound conformations using molecular dynamic simulations.
Results verified a more conformational flexible nature of HIV-Nef dimer in the absence of an
inhibitor.as compared to B9 bound conformation of HIV-Nef, which was found to be more
conformationally rigid with a lesser inter-dimeric association.
We believe that the results obtained from these several studies could be of great benefit in the
development of more effective therapeutic interventions for the treatment and cure of