A Hybrid Structure/Pharmacophore‐Based Virtual Screening Approach to Design Potential Leads: A Computer‐Aided Design of South African HIV‐1 Subtype C Protease Inhibitors

Abstract

Preclinical Research Virtual screening is the computational mirror image of high‐throughput screening and refers to the in silico evaluation of the biological activity of different molecular entities. Various virtual screening strategies and workflows have been adopted to enhance the process of identification of potential hits. Structure‐based scoring relies solely on the interactions between the ligand and the target protein. Conversely, pharmacophore‐based scoring relies on the shape complementation of each ligand candidate to a three‐dimensional reference ligand. Herewith, we report a systematic integrated hybrid approach, along with the use of well‐defined physicochemical and biological filters, to enhance high‐ranking hit structures complementing the binding site architecture while also mimicking the three‐dimensional features of known active ligands. With a lack of experimental data on the South African HIV protease enzyme (C‐SA HIV PR), very limited research has been conducted to design inhibitors against this enzyme variant. In this paper, a focused integrated structure‐ and pharmacophore‐based virtual screening protocol is introduced to identify potential leads to assist toward designing potent inhibitors against the C‐SA PR variant. This rapid and systematic approach can potentially be implemented for the design and discovery of inhibitors against a wide range of biological targets.

Hybrid Pharmacophoric Approach in the Design and Synthesis of Coumarin Linked Pyrazolinyl as Urease Inhibitors, Kinetic Mechanism and Molecular Docking

“…Coumarinyl pyrazolinyl thioamides 5a – 5q depict good intestinal solubility results compared to standard value (> 30% abs). Literature study showed that a compound with less than 30% absorbance value is considered as poorly absorbed compound . The skin permeability values of all compounds were also greater than standard value (−2.5 log K p ) which showed their significance as a good lead structures and justified their drug likeness behavior.…”

“…Literature study showed that a compound with less than 30% absorbance value is considered as poorly absorbed compound. [23] The skin permeability values of all compounds were also greater than standard value (À2.5 logK p ) which showed their significance as a good lead structures and justified their drug likeness behavior. Moreover, Blood Brain Barrier (BBB) and Central Nervous System (CNS) permeability values of all screened compounds were also comparable with the standard values (> 0.3 to <À1 log BB and >À2 to <À3 logPS), respectively.…”

“…Pyrazoline and its derivatives are the key structural motifs in heterocyclic chemistry and occupy important position in medicinal chemistry. They exhibited a spacious spectrum of pharmacological activities such as anticancer, antibacterial, antiviral, analgesic, anti‐inflammatory, antimalarial, antituberculosis, and anti‐fungal activities …”

NMR and Computational Methods in the Structural and Dynamic Characterization of Ligand-Receptor Interactions

“…The program generates initial 3D structures from a library of fragments, then it exhaustively enumerates all rotatable torsions using pre-defined libraries, and finally it samples this large conformational space using geometric and energy criteria. As an example, potential inhibitors of HIV-1 protease have been designed by the combination of conformational search with Omega and docking with Autodock [62].…”

Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore, virtual screening and molecular docking approaches for lead identification

“…The pharmacoinformatics approaches including structure activity relationship (SAR), pharmacophore, virtual screening and molecular docking have become pivotal techniques in the pharmaceutical industry for lead discovery. Many groups have applied the pharmacoinformatics approaches to identify inhibitors [23][24][25][26][27][28][29] against HIV protease. Hence the current study explores the binding preferences of the inhibitory molecules of HIV protease in terms of space modelling study and virtual screening along with molecular docking.…”