Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro.

Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively.

Proteasome as a Drug Target in Trypanosomatid Diseases.

Some diseases caused by trypanosomatid parasites, like Leishmaniasis, Chagas Disease, and Human African Trypanosomiasis (HTA), are challenging to manage, mainly concerning pharmacological therapy because they are associated with vulnerable populations. Unfortunately, there is a lack of significant investments in the search for new drugs. Therefore, one of the strategies to aid the discovery of new drugs is to identify and inhibit molecular targets essential to the parasite's survival, such as the proteasome, which degrades most proteins in the parasite cells. Our study has presented several proteasome inhibitors with various pharmacophoric cores, and two of them, 5, and 13, have stood out in the clinical phase of treatment for leishmaniasis.

CYP1B1: A Promising Target in Cancer Drug Discovery.

CYP1B1 plays an essential role in cancer's pathogenesis since it activates procarcinogens. Significantly, this enzyme catalyzes the hydroxylation of 17ß-estradiol, leading to carcinogenic metabolites involved in carcinogenesis and cancer progression. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target for chemotherapy. In addition, CYP1B1 is overexpressed in hormone-dependent cancer cells and could be related to resistance to anticancer drugs. However, the activity of CYP1B1 in the tumor microenvironment can metabolize and activate prodrugs in cancer cells, providing more selectivity and being useful for chemoprevention or chemotherapy strategies. Furthermore, due to its importance in anticancer drug design, recent studies have reported using computational methods to understand the intermolecular interactions between possible ligands and CYP1B1. Therefore, in this perspective, we highlight recent findings in developing CYP1B1 inhibitors (flavonoids, trans-stilbenes, estradiol derivatives, and carbazoles) and CYP1B1-activated prodrugs (a chalcone DMU-135 and an oxime DMAKO-20). Finally, we have analyzed their possible molecular interactions with this enzymatic target by molecular docking, which can help to design new active substances.

Molecular Targets for Chalcones in Antileishmanial Drug Discovery.

Leishmaniases are infectious diseases caused by flagellated protozoan parasites belonging to the genus Leishmania that infect cells of the mononuclear phagocytic system. These parasites are transmitted to humans by biting an infected female sandfly belonging to the genera Phlebotomus in the Old World and Lutzomyia in the New World. Despite representing a major public health problem, the therapeutic options are old and have several disadvantages. Given this scenario, developing vaccines or drugs for oral administration is necessary. Therefore, integrating computational and experimental strategies into the studies on molecular targets essential for the survival and virulence of the parasite is fundamental in researching and developing new treatments for leishmaniasis. In the effort to develop new vaccines and drugs, molecular docking methods are widely used as they explore the adopted conformations of small molecules within the binding sites of macromolecular targets and estimate the free energy of target-ligand binding. Privileged structures have been widely used as an effective model in medicinal chemistry for drug discovery. Chalcones are a common simple scaffold found in many compounds of natural and synthetic origin, where studies demonstrate the great pharmacological potential in treating leishmaniasis. This review is based on scientific articles published in the last ten years on molecular docking of chalcone derivatives for essential molecular targets of Leishmania. Thus, this review emphasizes how versatile chalcone derivatives can be used in developing new inhibitors of important molecular targets involved in the survival, growth, cell differentiation, and infectivity of the parasites that cause leishmaniasis.

In silico approaches and in vitro assays identify a coumarin derivative as antiviral potential against SARS-CoV-2.

COVID-19, a disease caused by SARS-CoV-2, was declared a pandemic in 2020 and created a global crisis in health systems, with more than 545 million confirmed cases and 6.33 million deaths. In this sense, this work aims to identify possible inhibitors of the SARS-CoV-2 RdRp enzyme using in silico approaches. RdRp is a crucial enzyme in the replication and assembly cycle of new viral particles and a critical pharmacological target in the treatment of COVID-19. We performed a virtual screening based on molecular docking from our in-house chemical library, which contains a diversity of 313 structures from different chemical classes. Nine compounds were selected since they showed important interactions with the active site from RdRp. Next, the ADME-Tox in silico predictions served as a filter and selected the three most promising compounds: a coumarin LMed-052, a hydantoin LMed-087, and a guanidine LMed-250. Molecular dynamics simulations revealed details such as changes in the positions of ligands and catalytic residues during the simulations compared to the complex from molecular docking studies. Binding free energy analysis was performed using the MMGBSA method, demonstrating that LMed-052 and LMed-087 have better affinities for the RdRp by energetic contributions to the stability of the complexes when compared to LMed-250. Furthermore, LMed-052 showed significant in vitro inhibition against MHV-3, decreasing 99% of viral titers. Finally, these findings are useful to guide structural modifications aiming to improve the potential of these compounds to act as inhibitors of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on Leishmania amazonensis.

Leishmaniasis is a neglected tropical disease caused by Leishmania species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal. Herein we report the synthesis and the biological activity evaluation against promastigote and amastigote forms of Leishmania amazonensis of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), 4f, was the most promising with an IC50 = 3.3 ± 0.34 µM (promastigotes), a low cytotoxicity profile (CC50 = 372.9 ± 0.04 µM), and a high selectivity index (SI = 112.6). Furthermore, 4f induced several morphological and ultrastructural changes in the free promastigote forms, loss of plasma membrane integrity, and increased reactive oxygen species (ROS). An in silico analysis of drug-likeness and ADME parameters suggested high oral bioavailability and intestinal absorption. Compound 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC50 value of 18.5 ± 1.19 µM. Molecular docking studies with targets, ARG and TR, showed that compound 4f had more hydrogen bond interactions with the ARG enzyme, indicating a more stable protein-ligand binding. These results suggest that 4,8-dimethoxynaphthalenyl chalcones are worthy of further study as potential antileishmanial drugs.