Discovery of HIV‐1 Integrase Inhibitors: Pharmacophore Mapping, Virtual Screening, Molecular Docking, Synthesis, and Biological Evaluation

Abstract

HIV-1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV-1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q(fit) value were used to design 30 molecules bearing pteridine ring and were docked on co-crystal structure of HIV-1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave-assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti-HIV activity against the replication of HIV-1 (IIIB) in MT-4 cells. The used approach of molecular docking and anti-HIV activity data of designed molecules will provide significant insights to discover novel HIV-1 Integrase Inhibitors.

Synthesis and structure determination of SCR7, a DNA ligase inhibitor

“…Both compounds have been previously shown to be active as nematocides, 5,6 and 1a has recently been shown to inhibit replication of HIV-1, although it is also toxic to host cells. 7 Synthesis and structure determination of pteridines…”

Development of HIV-1 integrase inhibitors: recent molecular modeling perspectives

“…Bhatt et al [45] obtained their best pharmacophore model using 20 structurally diversified chemical compounds, which contained four features as DDAH. The model was further validated with marketed inhibitors (Q fit = 84.25%) and test set compounds (Q fit = 96.39%), and the results showed good sensitivity and specificity (sensitivity = 0.78, specificity = 0.93).…”

“…In this situation, multiple receptor conformations would be recommended. Bhatt et al [45] The conformation of ligands also affects docking outcomes. Investigations have shown that docking outcomes vary depending on the input ligand conformation, and the inadequacy conformation search was the main cause of the poor performance [59].…”

“…Given that not all compounds could act as medication, the concept of drug-likeness has been introduced, two well-known examples of which are the 'Rule of Five' [81] and 'Rule of Three' [82], which are also widely used in the screening process of IN inhibitors [83][84][85]. After the application of Lipinski's Rule of Five, Bhatt et al [45] reduced the number of possible molecules from 39 179 to 17 930.…”

“…However, the performance was significantly improved when these methods were combined; optimal performance was received when human-based assessment of the ranking was added to the combining procedure, using some common chemical sense and previous experience with IN. Bhatt et al [45] devised a workflow of VS as follows: first, the best pharmacophore model was utilized as a 3D query to search the databases, and structures with bad fragments and counterions were removed; then, Lipinski's Rule of Five was applied; finally, docking was carried out for further filtering. VS can also be designed as a multistep process.…”