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Research and development of new Antiviral candidate drugs (HBV & Coronavirus), Drug Discovery, Medicinal Chemistry, Artificial Intelligence & Chemoinformatic.
MK-8591 (4’-ethynyl-2-fluoro-2’-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the...
Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisoster...
Here, we describe the design, synthesis, biological evaluation and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel Aryl-Phospho-Indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem assoc...
Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimizati...
We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substituti...
Provided herein are macrocyclic serine protease inhibitor compounds, for example, of Formula Ia or Ib, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.
Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in b...
Provided herein are 5,5-fused heteroarylene hepatitis C virus inhibitor compounds, for example, of Formula I, IA, or IB, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.
The invention relates to compounds of the general formula (I) wherein R1, R2, R3, R4, R5, R6, i and j have the meanings given in claim 1, and to the use thereof as caspase-10 inhibitors, especially for the treatment of diabetic retinopathy.
A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in...
A new concept, the Moleculer Hydration Probability (MHP), depending on the 3D structure of a molecule and on the composition of the first hydration shell, is presented. The knowledge of MHP allows the estimation of virtual log P on the van der Waals surface of molecules.
A new concept, the Molecular Hydration Probability (MHP), depending on the 3D structure of a molecule and on the composition of the first hydration shell, is presented. The knowledge of MHP allows the estimation of virtual log P on the van der Waals surface of molecules.
We present here a software that generates an extended connectivity matrix from the SMILES code of a molecule. This extended connectivity matrix allows the determination of the atomic code for an atomic fragment and then the attribution of its lipophilicity contribution fi. Then, log P can be easily computed by summing the fi values. This program wh...
Research and development of second generation Coronavirus polymerase inhibitors with wider coverge and better efficacy and tolerability.