The establishment of the epidermal barrier is essential for terrestrial vertebrate survival. Retroviral-like aspartic protease 1 (ASPRV1), also known as skin aspartic protease (SASPase), plays a central role in this process by facilitating the initial cleavage of profilaggrin into filaggrin monomers, which is vital for skin hydration and barrier integrity. Mutations disrupting this activity are linked to hereditary skin disorders. Evolutionarily, ASPRV1 originated from the domestication of an ancient retroviral sequence and comprises a Gag-like domain and a C-terminal protease domain. While it shares structural similarity with HIV-1 protease (HIV-1 PR), the molecular basis for its unique enzymatic properties and substrate specificity remains unclear. Here, we present the biochemical characterization and crystal structures of mature human ASPRV1 (ASPRV1-14) in multiple states, including wild-type, catalytically inactive mutants bound to self-cleavage and filaggrin peptides, and a complex with the HIV-1 PR inhibitor indinavir. Our results demonstrate that ASPRV1-14 exhibits an ionic strength-dependent monomer-dimer equilibrium, shifting from a low-activity monomer at low ionic strength to a high-activity dimer at high ionic strength. Structural analysis reveals that ASPRV1-14 possesses distinctly hydrophobic S2/S2' pockets, dictating a strict requirement for hydrophobic residues at the P2/P2' positions of substrates and explaining its resistance to most HIV-1 PR inhibitors, except indinavir. Furthermore, analysis of disease-associated mutations indicates two main pathogenic mechanisms: disrupting the S2/S2' pocket (e. g., V243A) or interfering with the self-cleavage maturation process (e. g., I186T, K199E, R311C/P, and P314T). Collectively, these findings provide a comprehensive molecular framework for understanding the roles of ASPRV1 in epidermal homeostasis and the pathogenesis of skin diseases, offering insights for future therapeutic development.

The proposed study is an integrated graph-theoretical and statistical model of predictive modeling and ranking of influenza strain drugs based on temperature-based topological indices. Chemical graphs were used to model drug molecules and regression models that estimated important physicochemical properties were derived. The cubic models had the best predictive ability with coefficients of determination up to [Formula: see text] of molar refractivity and polarity and [Formula: see text] of molar volume and moderate correlation of boiling and flash points ([Formula: see text]). Moreover, the multi-criteria decision-making methods (WSM and WPM) reported Azithromycin (81.25), Ritonavir (77.46), and Indinavir (72.82) as the best ranked ones. The presented solution will offer a cost-effective, interpretable, and reliable instrument of antiviral drug prioritization.

Zika virus (ZIKV) infection is associated with severe neurological complications, but no clinically approved antiviral therapies exist, leaving management reliant on symptomatic support. The essential NS2B/NS3 protease represents a promising drug target for ZIKV.

Mycobacterium tuberculosis (Mtb) remains a major global health threat due to its survival under host-induced stress and the rise of drug-resistant strains. One critical factor contributing to this resilience is its ability to efficiently repair DNA damage. To survive double-stranded DNA breaks, Mtb utilizes two pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). During dormancy, when HR is less active, Mtb predominantly relies on NHEJ, a pathway involving Ku and LigaseD. LigaseD catalyses DNA ligation through its ligase domain (LigDom), which comprises two subdomains: the NTase, harboring the ATP-binding site essential for adenylation, and the OB domain, which interacts with DNA. LigDom is highly conserved and exhibits low mutation rates in resistant strains, making it an attractive drug target. Using a structure-based drug repurposing approach, FDA-approved drugs were screened, identifying L-756423 as a potent inhibitor with a lowest binding free energy. Molecular dynamics simulation of the L-756423 bound LigDom complex reveals a stable domain structure with significant fluctuations in the interdomain region, suggesting movement in the OB domain that may support efficient binding. To validate these findings, Indinavir, a clinically approved HIV protease inhibitor with structural similarity to L-756423, was selected for experimental testing. Indinavir induces conformational flexibility in LigDom, and also competitively inhibits ATP binding thus blocking the adenylation. Functional microbiological assays confirmed that under oxidative stress, when NHEJ is critical, indinavir-treated cells displayed reduced survival, consistent with impaired DNA repair. These findings indicate that L-756423/Indinavir may hold therapeutic potential against latent tuberculosis and provide a rationale for further experimental investigation.

The Oropouche virus (OROV), an emerging arbovirus from the Peribunyaviridae family, represents a growing public health concern in Latin America, particularly due to its rapid urban spread and lack of specific treatments. In this study, we employed an integrated computational strategy combining molecular docking and molecular dynamics (MD) simulations to evaluate the potential of HIV protease inhibitors as candidates for repurposing against the Gc glycoprotein of OROV, a critical component in viral fusion and host cell entry. While docking initially ranked Saquinavir as the top binder, subsequent MD simulations revealed that nelfinavir and indinavir exhibited superior performance across multiple criteria, including binding energy, structural stability, center-of-mass distance maintenance, and consistent hydrogen bonding. These findings emphasize the limitations of docking-only approaches and highlight the importance of dynamic and energetic analyses for accurate inhibitor selection. The proposed computational pipeline demonstrates its value in identifying stable, high-affinity ligands and offers a promising route for accelerating drug discovery against neglected viral diseases such as OROV.

This review meticulously examines the development, design, and pharmacological assessment of both well known antiviral and antihypertensive medications all time employing new chemical techniques and structure-based drug design to design and synthesize vital therapeutic entities such as aliskiren (renin inhibitor), captopril (a2-ACE-Inhibitor), dorzolamide (inhibitor of carbonic anhydrase) the review demonstrates initial steps regarding the significance of stereoselective synthesis, metal chelating pharmacophores, and rational molecular properties. More importantly, protease inhibitors (i.e., saquinavir, ritonavir, indinavir, amprenavir, etc.) and more contemporary agents (i.e., oseltamivir, nirmatrelvir/ritonavir (Paxlovid), etc.) were identified in the review and form a basis of advancement in antiviral therapy. Using the above-mentioned computational applications (i.e., molecular dockings, structure-activity relationships (SAR)), quantitative structure-activity relationships (QSAR modeling), and ADMET profile information, selectivity, safety, and therapeutic reliability of compounds toward antiviral activity and antihypertensive activity have improved further as outcomes of drug discovery research. Through the combinatorial application of computational drug design and experimental chemistry, researchers have significantly optimized the drug discovery process, minimized off-target effects, and expedited the pathway to develop therapeutically useful medications. In conclusion, this review highlights the transformative power of interdisciplinary approaches, including structure-based design, computational modeling, and the emerging approaches of drug repurposing and virtual screening. This hybrid approach provides a greater opportunity to improve drug therapy for cardiovascular disease and viral infections, and represents the rewards of collaboration.

The HIV-1 protease inhibitor indinavir sulfate was cleaved via a one-pot reflux synthesis using 1-propanol, yielding the salt bis(2-hydroxy-2,3-dihydro-1H-inden-1-aminium) sulfate, 2C9H12NO[+]·SO4[2-]. Single-crystal X-ray diffraction (SC-XRD) revealed that the salt crystallizes in the monoclinic space group P21. The structure consists of two conformationally distinct cations and one sulfate anion, stabilized through an extensive hydrogen-bonding network. Thermal analysis showed minor solvent loss around 200 °C, followed by a two-step decomposition process commencing at 306.6 °C. Hirshfeld surface analysis revealed dominant O...H/H...O (44.4-41.0%) and H...H (45.2-40.1%) intermolecular contacts, with minor contributions from C...H/H...C and C...O/O...C interactions. These contact percentages were calculated for each of the two independent cations. The van der Waals surface area (687.30 Å[2]) accounts for 71.43% of the unit cell. These results provide structural and thermal evidence for the transformation of indinavir sulfate under alcoholytic conditions, highlighting the formation and stabilization of the resulting salt.

In Malaysia, the study on autism spectrum disorders (ASD) is limited. Most studies only focus on gene neuroligin 3 (NLGN3), NLGN4X, neurexin 1 (NRXN1) and SH3. This study focuses on the N-methyl-D-aspartate (NMDA) that was believed to have a significant effect on ASD. In this study, potential compounds and drugs that can restore receptor function in autistic patients were analysed. This research used an effective in silico method known as drug-repurposing to discover and rediscover drugs and analyse the binding of potential compounds or drugs to the NMDA receptor. AMPA and DOCK4 were used as controls in this study. Using a trusted server, Drug ReposER, 13 potential compounds or drugs that bind to NMDAR were identified. Then, proceed to the docking of potential compounds or drugs that bind to the NMDA receptor using Autodock Vina, Autodock, Hdock and CB dock and three drugs were selected that have the best binding score to NMDA, AMPA and DOCK4. The drugs were alitretinoin, salicylic acid and indinavir, respectively. Next, molecular dynamics simulations were performed with all selected compounds to study drug-protein binding, with detailed analysis of bond stability using root-mean-square fluctuation (RMSF) oscillations. Finally, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) predictions identify 4-androstenedione, tryptophan, carbocisteine and vitamin A as having minimal toxic effects. This study showed that alitretinoin, which was known to treat skin lesions from Kaposi's sarcoma, might have the ability to reverse the effect in ASD, particularly in NMDA receptors, potentially making a significant impact on the field of neurology and psychiatry.

Morphine and heroin dependence are growing concerns worldwide. Drug dependence is one of the greatest challenges, and developing alternative therapeutic strategies is essential. Due to few treatment options in pain management, morphine, a potent analgesic, is widely prescribed, but it carries a high risk of abuse. For the management of drug dependence, we have limited treatment options available, therefore, strategies should be developed to manage drug-seeking behaviors in clinical settings. We tried to find any FDA-approved drug targeting µ-opioid receptors through the in-silico approach. We screened around 186 FDA-approved drugs; we observed several drugs showing better docking scores with good affinity. We found vilazodone, indinavir, and lorazepam as potential drugs based on their affinity and mechanism of action. Later, these drugs were screened against human µ-opioid (PDB ID:8EF6) and other novel drug targets (5HT1 and TLR-4) that are associated with morphine dependence. Following docking, density functional theory (DFT), molecular dynamics (MD), molecular mechanics, and general born surface area (MM-GBSA) were performed to calculate the stability and ligand-protein binding free energies. Vilazodone, indinavir and lorazepam showed promising docking, MD, the energy gap between the HOMO and LUMO chemical reactivity, and MM-GBSA results compared to morphine and naloxone. We propose that these three drugs have huge potential to reverse the morphine and heroin dependence in diseased subjects near future.

In the ongoing effort to address viral diseases, the utilization of enzyme inhibitors targeting viral enzymes has emerged as a notable and effective strategy. The prevalence of hazardous and potentially fatal viral infections, such as Acquired Immunodeficiency Syndrome (AIDS), emphasizes the importance of exploring these inhibitors to advance healthcare solutions. This study conducts a comprehensive examination of the interaction between Indinavir and HIV protease, evaluating the functional efficacy of designed analogs based on Indinavir using docking tools. Quantum mechanics calculations are used for precise analysis of the structural and molecular properties of each designed analog. Additionally, ADMET studies for these compounds are examined to increase the evaluation of potential side effects and physicochemical properties. Molecular dynamics simulations are performed to deepen understanding and evaluate the inhibitory potential of these compounds on the protease enzyme. In conclusion, this comprehensive approach, integrating quantum mechanics calculations, ADMET screening, molecular docking, and molecular dynamics aims to enhance results in the development of antiviral candidates and refinement of existing drugs. Results introduce Lig12 as a designed compound that shows higher enzyme inhibition ability compared to Indinavir. This study emphasizes the importance of innovative drug design approaches in addressing the evolving challenges posed by viral infections. However, it is imperative to acknowledge the necessity for further experimental validations to verify the current findings and ensure their relevance.

The combined effort of medical, scientific and pharmaceutical research has transformed the HIV infection from an inevitably fatal disease into a manageable chronic ailment. Especially after the introduction of protease (PR) inhibitors the efficacy of the treatment regimen has been increased. However, the development of mutant PR enzymes is a major concern. The present study focuses on to understand the alterations in wild-type and mutants (D30N and L76V) PR structure by interaction of first-generation PR inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir. This information is extracted using molecular docking and MD simulation. Further, post-MD analysis such as RMSD, RMSF, PCA, DCCM, intermolecular interactions and binding free energy values calculation has been done. In comparison to L76V, D30N mutation affected the stable binding of the most of the studied PR inhibitors. The positively charged NH2 and thiazole group of amprenavir and nelfinavir is repelled by NH2 of Asn30 in D30N mutant. This repulsion pushes the drugs towards flap domain and causes flap opening. The MD simulation reveals that amprenavir, nelfinavir and saquinavir drugs have good compatibility with L76V mutant PR enzyme whereas indinavir was affected by the same. L76V mutant does not form any direct interaction with the first line drugs; hence the drugs forming strong interactions with the active site, flap domain and substrate binding region residues are quite enough to manage the resistance provided by L76V mutant. The results provided the insight into the drug-resistant or drug-susceptibility mechanism of L76V and D30N mutation against first-generation PR inhibitors.

We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and m/z 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC0-t of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.