This review aims to highlight the structures of ADAR proteins that have been crucial in the discernment of their functions and are relevant to future therapeutic development. ADAR proteins can correct or diversify genetic information, underscoring their pivotal contribution to protein diversity and the sophistication of neuronal networks. ADAR proteins have numerous functions in RNA editing independent roles and through the mechanisms of A-I RNA editing that continue to be revealed. Provided is a detailed examination of the ADAR family members—ADAR1, ADAR2, and ADAR3—each characterized by distinct isoforms that offer both structural diversity and functional variability, significantly affecting RNA editing mechanisms and exhibiting tissue-specific regulatory patterns, highlighting their shared features, such as double-stranded RNA binding domains (dsRBD) and a catalytic deaminase domain (CDD). Moreover, it explores ADARs’ extensive roles in immunity, RNA interference, and disease modulation, demonstrating their ambivalent nature in both the advancement and inhibition of diseases. Through this comprehensive analysis, the review seeks to underline the potential of targeting ADAR proteins in therapeutic strategies, urging continued investigation into their biological mechanisms and health implications.

Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from −81.304 to −1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (−1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [−873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) > 0.442 and probability of inactivity (Pi) < 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2.

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC₅₀ values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

Adenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules. Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore, targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating RNA editing and potentially treating associated pathologies. However, there are limited compounds that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<−9.5 kcal/mol) than the known inhibitor, 8-azanebularine (−6.8 kcal/mol). The topmost compounds were also observed to possess high binding affinity towards 5-HT_2CR with binding energies ranging from −7.8 to −12.9 kcal/mol. Further subjecting the top ADAR2–ligand complexes to molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577, ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies of −174.911, −137.369, −117.236, −67.023, and −64.913 kJ/mol, respectively, with the human ADAR2 protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights into the molecular interactions between ADAR2 and small molecules, aiding in the design of future ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified herein may be beneficial in treating several neurological disorders, cancers, viral infections, and inflammatory disorders caused by ADAR2 after experimental validation.

The prognosis of mixed-lineage leukemia (MLL) has remained a significant health concern, especially for infants. The minimal treatments available for this aggressive type of leukemia has been an ongoing problem. Chromosomal translocations of the KMT2A gene are known as MLL, which expresses MLL fusion proteins. A protein called menin is an important oncogenic cofactor for these MLL fusion proteins, thus providing a new avenue for treatments against this subset of acute leukemias. In this study, we report results using the structure-based drug design (SBDD) approach to discover potential novel MLL-mediated leukemia inhibitors from natural products against menin. The three-dimensional (3D) protein model was derived from Protein Databank (Protein ID: 4GQ4), and EasyModeller 4.0 and I-TASSER were used to fix missing residues during rebuilding. Out of the ten protein models generated (five from EasyModeller and I-TASSER each), one model was selected. The selected model demonstrated the most reasonable quality and had 75.5% of residues in the most favored regions, 18.3% of residues in additionally allowed regions, 3.3% of residues in generously allowed regions, and 2.9% of residues in disallowed regions. A ligand library containing 25,131 ligands from a Chinese database was virtually screened using AutoDock Vina, in addition to three known menin inhibitors. The top 10 compounds including ZINC000103526876, ZINC000095913861, ZINC000095912705, ZINC000085530497, ZINC000095912718, ZINC000070451048, ZINC000085530488, ZINC000095912706, ZINC000103580868, and ZINC000103584057 had binding energies of −11.0, −10.7, −10.6, −10.2, −10.2, −9.9, −9.9, −9.9, −9.9, and −9.9 kcal/mol, respectively. To confirm the stability of the menin–ligand complexes and the binding mechanisms, molecular dynamics simulations including molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations were performed. The amino acid residues that were found to be potentially crucial in ligand binding included Phe243, Met283, Cys246, Tyr281, Ala247, Ser160, Asn287, Asp185, Ser183, Tyr328, Asn249, His186, Leu182, Ile248, and Pro250. MI-2-2 and PubChem CIDs 71777742 and 36294 were shown to possess anti-menin properties; thus, this justifies a need to experimentally determine the activity of the identified compounds. The compounds identified herein were found to have good pharmacological profiles and had negligible toxicity. Additionally, these compounds were predicted as antileukemic, antineoplastic, chemopreventive, and apoptotic agents. The 10 natural compounds can be further explored as potential novel agents for the effective treatment of MLL-mediated leukemia.

Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers.