7WCQ

Crystal structure of HIV-1 protease in complex with lactam derivative 1

Summary for 7WCQ

• Entry DOI: 10.2210/pdb7wcq/pdb
• Descriptor: Protease, (3R,4R)-3-[(4-fluorophenyl)methyl]-1-[(4-methoxyphenyl)methyl]-3-(4-methylsulfonylphenyl)-4-oxidanyl-pyrrolidin-2-one (3 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus
• Total number of polymer chains: 1
• Total formula weight: 11314.33

Authors

Kojima, E.,Iimuro, A.,Nakajima, M.,Kinuta, H.,Asada, N.,Sako, Y.,Nakata, Z.,Uemura, K.,Arita, S.,Miki, S.,Wakasa-Morimoto, C.,Tachibana, Y.,Fumoto, M. (deposition date: 2021-12-20, release date: 2022-11-02, Last modification date: 2023-11-29)

Primary citation

Kojima, E.,Iimuro, A.,Nakajima, M.,Kinuta, H.,Asada, N.,Sako, Y.,Nakata, Z.,Uemura, K.,Arita, S.,Miki, S.,Wakasa-Morimoto, C.,Tachibana, Y.
Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.
J.Med.Chem., 65:6157-6170, 2022

PubMed 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 . The designed compound demonstrated weak but evident inhibitory activity (IC = 54 μM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound (IC = 0.0071 μM, EC = 0.86 μM), an almost 10,000-fold improvement in activity from . 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.

PubMed: 35416651
DOI: 10.1021/acs.jmedchem.1c02217

Experimental method

X-RAY DIFFRACTION (2.011 Å)