The rare zoonotic Borna disease virus (BDV) causes fatal neurological disease in various animals, with a high mortality rate exceeding 90% in central Europe. However, unlike most viruses, it establishes persistent infections within the host cell nucleus, hindering treatment. As successful BDV treatments remain elusive, the researchers turned to a computational approach, utilizing molecular docking, ADME/T, post-docking MMGBSA, MD simulation, DCCM, and PCA to identify promising phytochemical drug candidates targeting the BDV Nucleoprotein (PDB ID: 1N93). From IMPPAT 1940 unique phytochemical compounds of a total of 8617 compounds from 36 Indian medicinal plants were retrieved. Three compounds were chosen as leads with higher binding affinity of -6.244, -6.116, and -6.07 kcal/mol with CID 163114683 (IMPHY000668) Nimbochalcin, CID 20871246 (IMPHY007896) 3,4-Dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid, and CID 243 (IMPHY002962) Benzoic acid. The three top compounds coordinated with the protein’s common amino acid residues at GLN 161, ARG 165, ILE 145, ILE 162, ILE 149, and VAL 229 during molecular docking, which implies that both lead compounds and the control ligand interact within the protein’s shared active site. Afterwards, negative binding free energies of Nimbochalcin, 3,4-Dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid, and Benzoic acid were -51.21, -13.94, and -22.95 kcal/mol, accordingly. Favorable Pk and toxicological characteristics are shared by all of the chosen drugs, indicating their efficacy and safety. Using MD simulation, these three compounds were further assessed, and their stability in binding to the target protein was confirmed and subsequently, DCCM and PCA analyses were carried out from MD trajectory. MD simulations found that the protein binding site is highly stable when complexed with CID 20871246 and has a higher negative binding free energy value, indicating a strong interaction between the compound and the protein. Principal component analysis (PCA) identified three main components (PC1, PC2, and PC3) that accounted for 53.43%, 12.31%, and 5.97% of the variance, respectively. These findings provide intriguing evidence that the CID 20871246-1N93 complex is more stable than the other complexes. The BDV nucleoprotein was the target of this study’s investigation where CID 20871246 (3,4-dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid) exhibited tremendous antiviral activity which is found in the flower of the plant Mangifera indica revealing as a possible therapeutic candidate.

Proton pump inhibitors are essential for treating moderate-to-severe gastroesophageal reflux, peptic ulcers, esophagitis, and related conditions by increasing gastric pH and inhibiting hydrogen ion discharge into the stomach. However, prolonged use may lead to adverse effects along with reduced efficacy. Our research investigates the strategic modification of omeprazole (OMP) derivatives to improve their binding affinity to targeted proteins, thereby enhancing their chemical reactivity, stability, and toxicity profiles. A total of 22 novel OMP analogues were designed through structural alterations, focusing on the benzimidazole and pyridine rings. The geometrical attributes of the analogues were further confirmed through spectral and quantum computational analysis based on density functional theory (DFT) and a B3LYP/6-31G+ G (d, p) basis set. The molecular docking with PTAAC1 presented that most of the analogues had similar or higher binding affinities and nonbonding interactions, including OMP3, OMP19, and OMP21, with binding energies of -7.3, -8.3, and -8.1 kcal/mol compared to the OMP at -7.1 kcal/mol. Pharmacokinetic, biological, and toxicological profiles via ADMET and PASS predictions also demonstrated increased safety and therapeutic potential. MD simulation also showed good stability of OMP3, OMP19, and OMP21 in binding to PTAAC1, and the RMSD, RMSF, ligand RMSD, rGyr, SASA, MolSA, PolSA, and hydrogen bond analysis also suggested superior drug potential compared to OMP. Additionally, the post-simulation MM/GBSA analysis revealed that OMP3 (-36.91 kcal/mol) outperformed OMP19 (-26.45) and OMP21 (-12.61). The protein binding site’s high stability and elevated negative binding free energy value further indicate a robust compound-protein interaction with OMP3. However, principal component analysis (PCA) showed the highest variance for OMP21, accounting for 50.66%, 21.58%, and 6.51%, respectively, for PC1, PC2, and PC3. These findings could lead to the development of OMP3 and OMP21 as potential next-generation PPIs with enhanced pharmacological activity and improved side-effect profiles, necessitating more in vitro and in vivo testing.

West Nile virus is an arbovirus primarily spread by mosquitoes, which are the principal carriers and belong to the Flaviviridae category. This widespread disease lacks specific treatments despite its potential lethality, urgently demanding novel pharmaceutical research and development aims to prevent severe or long-term complications and improve overall outcomes. Pandemic awareness, increasing global incidence, fatal illness effects, expenses associated with outbreaks, reducing suffering, and other broader implications highlight the study’s wider significance. Drug design as a novel treatment approach to reduce the risk of resistance to the virus resulting from overuse of broad-spectrum antiviral therapies for unrelated viral diseases has been evaluated using computational techniques. Initially, molecular docking targeted the envelope glycoprotein of the WNV, utilizing a set of 5375 phytochemicals found in the IMPPAT database. Their binding affinities were −7.464, −5.802, −5.617, and −4.92, kcal/mol for CID: 359 (Phloroglucinol), 9064 (Cianidanol), 25310 (L-Rhamnose), and 492405 (Favipiravir), respectively. The lead compounds and the control ligand both bind at the common active site of the macro-molecule, as evidenced by their interactions with the same amino acid residues at LEU281, ASN47, THR282, SER29, MET48, MET46, and MET45, correspondingly. In post-docking MM-GBSA the negative binding energy of the P-L complex for the compounds CIDs: 359, 9064, 25310, and 492405 (control) were −29.16, −33.45, −32.02, and −3.16 kcal/mol, correspondingly. The selected compounds are secure and efficient since they demonstrate excellent toxicological and Pk characteristics. The compounds were further evaluated to confirm their stability and binding affinity to the target protein by molecular dynamics simulation (RMSD, RMSF, Rg, SASA, H-bond, P-L, and L-P contact). Following this, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) studies were conducted using the MD trajectory data. The ligands evaluated in this study demonstrated considerable stability of the proteins’ binding site when complexed with CID: 9064 and CID: 25310, respectively, in the MD simulation, which also revealed a high negative binding free energy value, indicating a robust interaction between the target and lead compounds. The three principal components (PC1, PC2, PC3) for the lead compounds corresponding to CID: 9064 (40.37%, 23.02%, and 8.82%) and CID: 25310 (73.04%, 10.06%, and 3.77%), respectively, indicate that their complexes are more stable than the other L-P complexes. Consequently, both the compounds derived from the plants Tamarindus indica and Plantago ovate, respectively, may potentially impede the viral activity of the WNV envelope glycoprotein, indicating the possibility of these compounds as prospective phytochemical therapeutic candidates. This preclinical study can be used in further drug development processes, including in vivo studies and animal trials.

Colorectal cancer (CRC) poses a significant global health issue. It ranks as the third most common type of cancer and the second leading cause of cancer-related deaths. Among the molecular factors driving its progression, cyclin-dependent kinase 2 (CDK2) plays a key role. CDK2 is a protein kinase essential for regulating the cell cycle, and its dysregulation is implicated in the development of various cancers, notably CRC. Fruquintinib is an already available drug against CRC. However, this study is being performed in search of better drug-like compounds. Some studies have shown that phytochemicals are less toxic and have fewer adverse effects than commercially available medications. With the vision of detecting CDK2 inhibitors, phytochemicals with anticancer activity can be used as alternatives to develop the drug candidate. Cheminformatics-based analysis is used for this purpose. This approach includes molecular docking, adsorption, distribution, metabolism, excretion/toxicity (ADME/T), post-docking molecular mechanism generalized born surface area (MM-GBSA), structural activity relationship (SAR), frontier molecular orbital (FMO), and molecular dynamics (MD) simulations. Molecular docking was employed to determine the binding strength of 4433 phytochemicals with anti-cancer properties sourced from the IMPPAT database. The top five candidates, CIDs-135438111, 6474893, 44257567, 10469828, and 353825, were selected based on their docking scores. Later, three lead compounds, CIDs-6474893, 10469828, and 135438111, were finalized depending on their favorable ADME/T profiles. All three selected pharmaceuticals demonstrated excellent post-dock MM-GBSA scores and HOMO-LUMO energy gaps, which served as confirmation of their efficacy and safety. The SAR analysis also revealed anti-mutagenic, antineoplastic, and apoptosis-inducing properties of the compounds. Finally, the rigidity of the protein-ligand complex structures was verified by MD simulations. Overall, the study suggests these three phytochemicals exhibit stronger binding and better pharmacological profiles than the control (fruquintinib), offering a promising direction for CRC treatment development.