Discovery of novel RARα agonists using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulation studies.

Nuclear retinoic acid receptors (RARs) are ligand-dependent transcription factors involved in various biological processes, such as embryogenesis, cell proliferation, differentiation, reproduction, and apoptosis. These receptors are regulated by retinoids, i.e., retinoic acid (RA) and its analogs, as receptor agonists. RAR agonists are promising therapeutic agents for the treatment of serious dermatological disorders, including some malignant conditions. By inducing apoptosis, they are able to inhibit the proliferation of diverse cancer cell lines. Also, RAR agonists have recently been identified as therapeutic options for some neurodegenerative diseases. These features make retinoids very attractive molecules for medical purposes. Synthetic selective RAR agonists have several advantages over endogenous ones, but they suffer poor pharmacokinetic properties. These compounds are normally lipophilic acids with unfavorable drug-like features such as poor oral bioavailability. Recently, highly selective, potent, and less toxic RAR agonists with proper lipophilicity, thus, good oral bioavailability have been developed for some therapeutic applications. In the present study, ligand and structure-based virtual screening technique was exploited to introduce some novel RARα agonists. Pharmacokinetic assessment was also performed in silico to suggest those compounds which have optimized drug-like features. Finally, two compounds with the best in silico pharmacological features are proposed as lead molecules for future development of RARα agonists.

New 2-alkylthio-1-benzylimidazole-5-carboxylic acid derivatives targeting gp41: design, synthesis and in vitro anti-HIV activity evaluation.

Background Although current available medications have increased the quality of life in HIV-infected patients, there are still some shortcomings in HIV treatment arising from viral resistance, drug side effects and high cost of medication. Therefore, there is an urgent need for some suitable HIV inhibitors with different mechanisms of action. Gp41, located on the HIV cell surface, plays an important role in the fusion of viral and host cell membranes. With the same structure in different HIV strains, gp41 seems to be a promising target for developing novel HIV fusion inhibitors. Objective Based on the essential structural elements of gp41 inhibitors, two series of compounds were prepared and their inhibitory effect on HIV cell growth was investigated. Compared to the known small-molecule gp41 inhibitors, 2-Alkylthio-1-benzylimidazole-5-carboxylic acid (series I) and (E)-4-{[5-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxyimino)methyl)-2-(alkylthio)-1H-imidazol-1-yl]methyl}benzoic acid derivatives (series II) had more flexible skeleton with extra moieties interacting with the gp41 key residues. Method In silico drug design approaches including molecular docking and molecular dynamics simulations were employed to design these novel compounds prior to preparation. The designed compounds exhibited proper chemical interactions and stable complexes with gp41. Then, the selected candidates were efficiently synthesized, and their anti-HIV-1 and anti-HIV-2 activities, as well as their cellular cytotoxicity in MT-4 cells were determined. Results None of the compounds belonging to the series I were active against HIV-1 and HIV-2 replication in cell cultures, and most of the compounds in series II exhibited significant cytotoxicity against MT-4 cells in low micro molar concentrations. Conclusion The smaller molecular structures of the compounds in series I might be responsible for their poor anti-HIV effects. The high toxicity of the series II compounds on the host cell makes it impossible to assess their anti-HIV activities.

Molecular dynamics simulation, 3D-pharmacophore and scaffold hopping analysis in the design of multi-target drugs to inhibit potential targets of COVID-19.

SARS-CoV-2 has posed serious threat to the health and has inflicted huge costs in the world. Discovering potent compounds is a critical step to inhibit coronavirus. 3CLpro and RdRp are the most conserved targets associated with COVID-19. In this study, three-dimensional pharmacophore modeling, scaffold hopping, molecular docking, structure-based virtual screening, QSAR-based ADMET predictions and molecular dynamics analysis were used to identify inhibitors for these targets. Binding free energies estimated by molecular docking for each ligand in different binding sites of RdRp were used to predict the active site. Previously reported active 3CLpro and RdRp inhibitors were used to build a pharmacophore model to develop different scaffolds. Structure-based simulations and pharmacophore modeling based on Hip Hop algorithm converged in a state that suggest hydrogen bond acceptor and donor features have a critical role in the two binding sites. Further validations indicated that the best pharmacophore model has fairly good correlation values compared with approved inhibitors. Structure-based simulation results approved that GLu166 and Gln189 in 3CLpro and Lys551 and Glu811 in RdRp, are critical residues for dual activities. Ten compounds were extracted from pharmacophore-based virtual screening in six databases. The results, gained by repurposing approach, suggest the effectiveness of these ten compounds with different scaffolds as possible inhibitors of the two targets. Some quinoline-based hybrid derivatives also were designed. QSAR descriptors plot predicted that the scaffolds have had accepted pharmacokinetic profiles. Multiple molecular dynamics simulations in 100 ns and MM/PBSA studies of some reference inhibitors and the novel compounds in complex with both targets demonstrated stable complexes and confirmed the interaction modes. Based on different computational methods, COVID-19 multi-target inhibitors are proposed. Communicated by Ramaswamy H. Sarma.

Synthesis, Molecular Docking and Molecular Dynamics Simulation of 2- Thioxothiazolidin-4-One Derivatives against Gp41.

INTRODUCTION: Gp41 and its conserved hydrophobic groove on the N-terminal heptad repeat region are attractive targets in the design of HIV-1 entry inhibitors. Linearly extended molecules have shown potent anti-HIV-1 activity for their effective interactions with the gp41 binding pocket. Rhodanine ring attached to substituted pyrrole or furan rings has been proved a preferred moiety to be inserted inside the molecular structure of the gp41 inhibitors. OBJECTIVES: Based on the previous findings we are going to describe some rhodanine derivatives in which a substituted imidazole ring is introduced in place of the pyrrole or furan rings. The compounds' flexibility is increased by inserting methylene groups inside the main scaffold. METHODS: Molecular docking and molecular dynamics simulations approaches were exploited to investigate the chemical interactions and the stability of the designed ligands-gp41 complex. All compounds were synthesized and their chemical structures were elucidated by 1HNMR, 13CNMR, FTIR and Mass spectroscopy. Biological activities of the compounds against HIV-1 and HIV-2 and their cellular toxicities against the T-lymphocyte (MT-4) cell line were determined. RESULTS: All the designed compounds showed proper and stable chemical interactions with gp41 according to the in silico studies. The results of the biological tests proved none of the compounds active against HIV-1 replication in cell cultures. CONCLUSION: Since all the studied compounds were potently toxic for the host cell; it was therefore not possible to assess their anti-HIV activities.

Gp41 inhibitory activity prediction of theaflavin derivatives using ligand/structure-based virtual screening approaches.

Gp41 and its conserved hydrophobic groove on the NHR region is one of the attractive targets in the design of HIV-1 entry inhibitory agents. This hydrophobic pocket is very critical for the progression of HIV and host cell fusion. In this study different ligand-based (structure similarity search) and structure-based (molecular docking and molecular dynamic simulation) methods were performed in a virtual screening procedure to select the best compounds with the most probable HIV-1 gp41 inhibitory activities. In silico pharmacokinetics and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties filtration also was considered to choose the compounds with best drug-like properties. The results of molecular docking and molecular dynamic simulations of the final selected compounds showed suitable stabilities of their complexes with gp41. The final selected hits could have better pharmacokinetics properties than the template compound, theaflavin digallate (TF3), a naturally-originated potent gp41 inhibitor.

HIV-1 Entry Inhibitors: A Review of Experimental and Computational Studies.

The HIV-1 life cycle consists of different events, such as cell entry and fusion, virus replication, assembly and release of the newly formed virions. The more logical way to inhibit HIV transmission among individuals is to inhibit its entry into the immune host cells rather than targeting the intracellular viral enzymes. Both viral and host cell surface receptors and co-receptors are regarded as potential targets in anti-HIV-1 drug design process. Because of the importance of this topic it was decided to summarize recent reports on small-molecule HIV-1 entry inhibitors that have not been considered in the latest released reviews. All the computational studies reported in the literature regarding HIV-1 entry inhibitors since 2014 was also considered in this review.