Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template

Abstract

A novel strategy for lead identification that we have dubbed the “Pocket-to-Lead” strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized in silico. The designed compound 9 demonstrated weak but evident inhibitory activity (IC50 = 54 μM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound 14 (IC50 = 0.0071 μM, EC50 = 0.86 μM), an almost 10,000-fold improvement in activity from 9. The structure of the designed molecules proved to be novel with high synthetic feasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore.

Structure-Based Identification of Organoruthenium Compounds as Nanomolar Antagonists of Cannabinoid Receptors

“…Although compounds 1 and 2 with the basic scaffold did not show detectable binding activity against cannabinoid receptors, they formed considerable interactions with protein residues and served as good starting points for further structure-based optimization. Utilizing structure-based strategies, several other studies have also reported that high-affinity compounds can be developed by starting from weak or even false hits, forming key interactions with the binding pockets. − This study illustrated the potential of reverse docking for exploring novel chemical spaces in drug discovery, thereby expanding its utility. Using the SBDD strategy, we expect to attempt various organometallic compounds with kinetically inert scaffolds in the CSD so that novel chemical space can be explored against different targets.…”

Fragment-to-Lead Medicinal Chemistry Publications in 2022

“…Interestingly, the two entries (2 and 3) both used virtual screening for hit finding, similar to the protein kinase A example, thereby perhaps illustrating the growing understanding of the binding site for this class of enzymes. 12,13 Specifically, HIV-1 protease has been a pharmaceutical target for decades, and SARS CoV-2 Mpro has received massive Oversized composed float in tbl2 (504pt x 1227.5858pt) -Float Skipped attention, which has led to the rapid development of Paxlovid, a drug targeting this viral protease. 37,38 Enzymes (Other).…”

A phenoxy-bridged trinuclear Ni(ii) complex: synthesis, structural elucidation and molecular docking with viral proteins

“…The HIV-1 protease (PDB ID: 7WCQ) was also selected for molecular docking and its crystal was also retrieved from the Protein Data Bank and used as the receptor protein. 47 Redocking has also been performed to validate our molecular docking protocols. Initially, the protein coordinates were prepared by deleting all the water and heteroatoms to make the targeted protein receptor-free.…”