In silico design and computational evaluation of novel 2-arylaminopyrimidine-based compounds as potential multi-targeted protein kinase inhibitors: application for the native and mutant (T315I) Bcr-Abl tyrosine kinase.

An integrated computational approach to drug discovery was used to identify novel potential inhibitors of the native and mutant (T315I) Bcr-Abl tyrosine kinase, the enzyme playing a key role in the pathogenesis of chronic myeloid leukemia (CML). This approach included i) design of chimeric molecules based on the 2-arylaminopyrimidine fragment, the main pharmacophore of the Abl kinase inhibitors imatinib and nilotinib used in the clinic for the CML treatment, ii) molecular docking of these compounds with the ATP-binding site of the native and mutant Abl kinase, iii) refinement of the ligand-binding poses by the quantum chemical method PM7, iv) molecular dynamics simulations of the ligand/Abl complexes, and v) prediction of the ligand/Abl binding affinity in terms of scoring functions of molecular docking, machine learning, quantum chemistry, and molecular dynamics. As a result, five top-ranking compounds able to effectively block the enzyme catalytic site were identified. According to the data obtained, these compounds exhibit close modes of binding to the Abl kinase active site that are mainly provided by hydrogen bonds and multiple van der Waals contacts. The identified compounds show high binding affinity to the native and mutant Abl kinase comparable with the one calculated for the FDA-approved kinase-targeted inhibitors imatinib, nilotinib, and ponatinib used in the calculations as a positive control. The results obtained testify to the predicted drug candidates against CML may serve as good scaffolds for the design of novel anticancer agents able to target the ATP-binding pocket of the native and mutant Abl kinase.Communicated by Ramaswamy H. Sarma.

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease.

A computational approach to in silico drug discovery was carried out to identify small drug-like compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (MPro). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-MPro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 MPro were generated by molecular docking, quantum chemical calculations and molecular dynamics simulations. At the final point, analysis of the interaction modes of the identified compounds with MPro and prediction of their binding affinity were carried out. Calculation revealed 5 top-ranking compounds that exhibited a high affinity to the active site of SARS-CoV-2 MPro. Insights into the ligand - MPro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 MPro, in line with the low values ​​of binding free energy and dissociation constant. Mechanism of binding of these compounds to MPro is mainly provided by van der Waals interactions with the functionally important residues of the enzyme, such as His-41, Met-49, Cys-145, Met-165, and Gln-189 that play a role of the binding hot spots assisting the predicted molecules to effectively interact with the MPro active site. The data obtained show that the identified X77-mimetic candidates may serve as good scaffolds for the design of novel antiviral agents able to target the active site of SARS-CoV-2 MPro.Communicated by Ramaswamy H. Sarma.

In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4.

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.

In silico design of novel broad anti-HIV-1 agents based on glycosphingolipid ß-galactosylceramide, a high-affinity receptor for the envelope gp120 V3 loop.

Novel anti-Human immunodeficiency virus (HIV)-1 agents targeting the V3 loop of envelope protein gp120 were designed by computer modeling based on glycosphingolipid ß-galactosylceramide (ß-GalCer), which is an alternative receptor allowing HIV-1 entry into CD4-negative cells of neural and colonic origin. Models of these ß-GalCer analogs bound to the V3 loops from five various HIV-1 variants were generated by molecular docking and their stability was estimated by molecular dynamics (MDs) and binding free energy simulations. Specific binding to the V3 loop was accomplished primarily by non-conventional XH…π interactions between CH/OH sugar groups of the glycolipids and the conserved V3 residues with π-conjugated side chains. The designed compounds were found to block the tip and/or the base of the V3 loop, which form invariant structural motifs that contain residues critical for cell tropism. With the MDs calculations, the docked models of the complexes of the ß-GalCer analogs with V3 are energetically stable in all of the cases of interest and exhibit low values of free energy of their formation. Based on the data obtained, these compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.

Structural analysis of the envelope gp120 V3 loop for some HIV-1 variants circulating in the countries of Eastern Europe.

The V3 loop on gp120 from human immunodeficiency virus type 1 (HIV-1) is a focus of many research groups involved in anti-AIDS drug development because this region of the protein is a principal target for neutralizing antibodies and a major determinant for cell tropism and syncytium formation. In this study, the nucleotide sequences of the env gene region coding the V3 loop were determined by DNA sequencing methods for four novel HIV-1 strains that circulate in the countries of Eastern Europe, such as Russia, Belarus, Ukraine, etc. Based on the empirical data obtained, the 3D structures of the V3 loops associated with these viral modifications were generated by computer modeling and then compared to discover similarities in the spatial arrangement of this functionally important site of gp120. Despite the HIV-1 genetic variety, several regions of the V3 loop that contain residues critical for cell tropism were shown to be structurally invariant, which may explain its exceptional role in a co-receptor usage. These data together with those on the biological activity of the V3 individual residues clearly show that these conserved structural motifs of gp120 represent potential HIV-1 weak points most suitable for therapeutic intervention.