Mechanistic insights and in silico studies on selected G protein-coupled receptors implicated in HIV and neurological disorders.
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Date
2021
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Abstract
G protein-coupled receptors (GPCRs) are the largest membrane protein receptor superfamily
involved in a wide range of physiological processes. GPCRs form the major class of drug
targets for a diverse array of pathophysiological conditions. Consequently, GPCRs are
recognised as drug targets for the treatment of various diseases, including neurological
disorders, cardiovascular conditions, oncology, diabetes, and HIV. The recent advancement in
GPCR structure resolutions has provided novel avenues to understand their molecular basis of
signal transduction, ligand recognition and ligand-receptor interactions. These advances
provide a framework for the structure-based discovery of new drugs in targeting GPCRs
implicated in the pathogenesis of various human diseases.
In this thesis, the interactions of inhibitors at two dopamine receptor subtypes and C-C
chemokine receptor 5 (CCR5) of the Class A GPCR family were investigated. Dopamine
receptors and CCR5 are validated GPCR targets implicated in neurological disorders and HIV
disease, respectively. The lack of structural information on these receptors limited our
comprehension of their antagonists’ structural dynamics and binding mechanisms. The recently
solved crystal structures for these receptors have necessitated further investigations in their
ligand-receptor interactions to obtain novel insights that may assist drug discovery towards
these receptors.
This thesis comprehensively investigated the binding profiles of atypical antipsychotics (class
I and class II) at the first crystal structure of the D2 dopamine receptor (D2DR). The class I
antipsychotics exhibited binding poses and dynamics different from the class II antipsychotics
with disparate interaction mechanistic at D2DR active site. The class II antipsychotics were
remarkably observed to establish a recurrent and vital interaction with Asp114 via strong
hydrogen bond interactions. Furthermore, compared to class I antipsychotics, the class II
antipsychotics were found to engage favourably with the deep hydrophobic pocket of D2DR.
In addition, the structural basis and atomistic binding mechanistic of the preferential selective
inhibition at D3DR over D2DR were explored. This study investigated two small molecules
(R-VK4-40 and Y-QA31) with substantial selectivity (> 180-fold) for D3DR over D2DR. The
selective antagonists adopted shallow binding modes at D3DR while demonstrating a deep
hydrophobic pocket binding at D2DR. Also, the vital roles and contribution of critical residues
to the selective binding of R-VK4-40 and Y-QA31were identified in D3DR. Structural and
binding free energy analyses further discovered distinct stabilising effects of the selective
antagonists on the secondary architecture and binding profiles of D3DR relative to D2DR.
Furthermore, the atomistic molecular interaction mechanism of how slight structural
modification between novel derivatives of 1-heteroaryl-1,3-propanediamine (Compd-21 and -
34) and Maraviroc significantly affects their binding profiles toward CCR5 were elucidated.
This study utilised explicit lipid bilayer molecular dynamics (MD) simulations and advanced
analyses to explore these inhibitory disparities. The thiophene moiety substitution common to
Compd-21 and -34 was found to enhance their CCR5-inhibitory activities due to
complementary high-affinity interactions with residues critical for the gp120 V3 loop binding.
The study further highlights the structural modifications that may improve inhibitor
competitiveness with the gp120 V3 loop.
Finally, structure-based virtual screening of antiviral chemical database was performed to
identify potential compounds as HIV-1 entry inhibitors targeting CCR5. The identified
compounds made pertinent interactions with CCR5 residues critical for the HIV-1 gp120-V3
loop binding. Their predicted in silico physicochemical and pharmacokinetic descriptors were
within the acceptable range for drug-likeness. Further structural optimisations and biochemical
testing of the proposed compounds may assist in the discovery of novel HIV-1 therapy.
The studies presented in this thesis provide novel mechanistic and in silico perspective on the
ligand-receptor interactions of GPCRs. The findings highlighted in this thesis may assist in
further research towards the identification of novel drug molecules towards CCR5 and D2-like
dopamine receptor subtypes.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.