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Rheumatoid arthritis is a common chronic disabling inflammatory disease that is characterized by inflammation of the synovial membrane and leads to discomfort. In the current study, twenty-seven 1,6-disubstituted 1 H -pyrazolo[3,4- d ]pyrimidines were tested as potential selective inhibitors of the tyrosine-protein kinase JAK3 using a number of molecular modeling methods. The activity of the screened derivatives was statistically quantified using multiple linear regression and artificial neural networks. To assess the quality, robustness, and predictability of the generated models, the leave-one-out cross-validation method was applied with favorable results (Q 2 = 0.75) and Y-randomization. In addition, the evaluation of the predictive ability of the established model was confirmed by means of an external validation using a composite test set and an applicability domain approach. The covalent docking indicated that the tested 1 H -pyrazolo[3,4- d ]pyrimidines containing the acrylic aldehyde moiety had irreversible interaction with the residue Cys909 in the active sites of the tyrosine-protein kinase JAK3 by Michael addition. The molecular dynamics for three selected derivatives (compounds 9 , 12 , and 18 ) were used to verify the covalent docking by determining the stability of hydrogen bonding interactions with active sites, which are needed to stop tyrosine-protein kinase JAK3. The results obtained showed that the tested compounds containing acrylic aldehyde moiety had favorable binding free energies, indicating a strong affinity for the JAK3 enzyme. Overall, this current study suggests that the tested compounds containing the acrylic aldehyde moiety have the potential to act as anti-JAK3 inhibitors. They could be explored further to be used as treatment options for rheumatoid arthritis.Communicated by Ramaswamy H. Sarma.

A detailed multistep framework combining quantitative structure-activity relationship, global reactivity, absorption, distribution, metabolism and elimination properties, molecular docking and molecular dynamics simulation (MD) on a series of Selective Estrogen Receptor Down-Regulators (SERDs) interacting with Estrogen Receptor α (ERα) has been performed. The partial least squares regression method derived an empirical model with better predictive capability. The results of global reactivity descriptors revealed that all the compounds are considered strong electrophiles, allowing them to participate in polar reactions more easily. The Brain Or IntestinaL EstimateD permeation diagram revealed that compounds 49 and 31 were predicted to be well absorbed by the human gastrointestinal tract and would not enter the brain. The elucidation of the binding mode between the most active compounds that comply with Lipinski's and Veber's rules from the dataset and ERα targets was explored by molecular docking. The MD simulations were performed for 100 ns on the best compounds, which indicated their stability state under dynamics simulations. These findings are expected to help predict the anticancer activities of the studied SERD compounds and better understand their binding mechanism with ERα targets.Communicated by Ramaswamy H. Sarma.

The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions confirmed cases and hundreds of thousands death cases around the world so far. Molecular docking combined with molecular dynamics is one of the most important tools of drug discovery and drug design, which it used to examine the type of binding between the ligand and its protein enzyme. Global reactivity has important properties, which enable chemists to understand the chemical reactivity and kinetic stability of compounds. In this study, molecular docking and reactivity were applied for eighteen drugs, which are similar in structure to chloroquine and hydroxychloroquine, the potential inhibitors to angiotensin-converting enzyme (ACE2). Those drugs were selected from DrugBank. The reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2 and [SARS-CoV-2/ACE2] complex receptor in two active sites to find a ligand, which may inhibit COVID-19. The results obtained from this study showed that Ramipril , Delapril and Lisinopril could bind with ACE2 receptor and [SARS-CoV-2/ACE2] complex better than chloroquine and hydroxychloroquine. This new understanding should help to improve predictions of the impact of such alternatives on COVID-19.Communicated by Ramaswamy H. Sarma.

Conformational analysis of 18-ring membered macrolactones has been carried out using molecular mechanics calculations and molecular dynamics. A high conformational flexibility of macrolactones was obtained, and an important stereoselectivity was observed for the complexed macrolides. For 18d macrolactone, which was presented by a most favored conformer with 20.1% without complex, it was populated with 50.1% in presence of Fe(CO)3.