Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Abstract

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2–S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies

“…Opening of epoxide 9 with various benzyl amine derivatives provided amines 18 a , b . These amines were coupled with acids 4 a , 4 b , 7 a or 7 b , using EDCI and HOBt in the presence of DIPEA to provide the final compounds 3 i – n (Table ). Inhibitor 20 was synthesized starting from acetophenone derivative 19 following reported procedures…”

Classification of HIV-1 Protease Inhibitors by Machine Learning Methods

“…Figure 3 b depicts the structure and interactions between the ligand 8FP and protease (PDB code: 5UOV). 27 The ligand has shown K i of 0.025 nM with the enzyme. 27 The oxygen atom of the hydroxy group forms two hydrogen bonds with Asp 25 at two sites of amino acids chain.…”

“… 27 The ligand has shown K i of 0.025 nM with the enzyme. 27 The oxygen atom of the hydroxy group forms two hydrogen bonds with Asp 25 at two sites of amino acids chain. The oxygen atom of the acylamino group forms a hydrogen bond with Asp 29 at chain B.…”

“…To evaluate the predictive ability of the models, the external validation set was also predicted by the models. The external validation set included 35 750 decoys derived from the DUD database and 239 active inhibitors from the recent literature. − …”

Proteases: Pivot Points in Functional Proteomics

“…HIV protease inhibitors show off-target interference with proteases required for maturation of SREBP-1, a transcription factor that regulates gene expression in lipogenesis, with as result lipodystrophy syndrome; and blocking of glucose transporter-4 with as result insulin resistance; inhibition of the proteasome, resulting in metabolic complications, increased ER stress and autophagy; and caspase-dependent apoptosis, the discovery of which triggered interest in HIV protease inhibitors as potential anticancer drugs. The emergence of HIV-1 strains that are resistant to the current protease inhibitor drugs prompted the design of novel compounds with broad-spectrum activity against these variants [217,218]. Small non-peptide molecules with substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for binding to the S2-S3 specificity site, and flexible macrocyclic P1’-P2’ tethers were good candidates, with inhibition constants ( K i ) and IC 50 values in the nanomolar range.…”