Identification of lead inhibitors for 3CLpro of SARS-CoV-2 target using machine learning based virtual screening, ADMET analysis, molecular docking and molecular dynamics simulations.

The SARS-CoV-2 3CLpro is a critical target for COVID-19 therapeutics due to its role in viral replication. We employed a screening pipeline to identify novel inhibitors by combining machine learning classification with similarity checks of approved medications. A voting classifier, integrating three machine learning classifiers, was used to filter a large database (∼10 million compounds) for potential inhibitors. This ensemble-based machine learning technique enhances overall performance and robustness compared to individual classifiers. From the screening, three compounds M1, M2 and M3 were selected for further analysis. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis compared these candidates to nirmatrelvir and azvudine. Molecular docking followed by 200 ns MD simulations showed that only M1 (6-[2,4-bis(dimethylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carbonyl]-1H-pyrimidine-2,4-dione) remained stable. For azvudine and M1, the estimated median lethal doses are 1000 and 550 mg kg-1, respectively, with maximum tolerated doses of 0.289 and 0.614 log mg per kg per day. The predicted inhibitory activity of M1 is 7.35, similar to that of nirmatrelvir. The binding free energy based on Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) of M1 is -18.86 ± 4.38 kcal mol-1, indicating strong binding interactions. These findings suggest that M1 merits further investigation as a potential SARS-CoV-2 treatment.

Identification of potent inhibitors of HDAC2 from herbal products for the treatment of colon cancer: Molecular docking, molecular dynamics simulation, MM/GBSA calculations, DFT studies, and pharmacokinetic analysis.

The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, Rg, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.

Bacteriological Profile and Drug Susceptibility in Mucosal type Chronic Suppurative Otitis Media.

BACKGROUND: In Chronic Suppurative Otitis Media, mucosal type, most common organisms are Pseudomonas aeruginosa and Proteus species (P. mirabilis and P. vulgaris). It is important to prescribe culture-directed antibiotics to prevent resistance. This study was conducted to determine the bacteriological profile and drug susceptibility in patient with chronic suppurative otitis media. METHODS: This is a hospital-based descriptive study done at Gandaki Medical College, Pokhara, Nepal from July 2019 to June 2020. Under aseptic condition, the swab specimens were obtained from patients with history of ear discharge of >12 weeks duration and findings central perforation of the tympanic membrane. The sample was labeled and immediately transferred to the microbiology lab for culture/sensitivity test according to the guidelines of the Clinical and Laboratory Standards Institute. RESULTS: Out of total 127 patients, 48 (37.8%) were male and 79 (62.2%) were female. One hundred and seven samples (84.3%) had positive culture while 20 samples (15.7%) had no growth. Staphylococcus aureus (43%), was the most common isolate followed by Pseudomonas aeruginosa (23.4%), Proteus mirabilis (9.3%), and Escherichia coli (8.4%). All the organisms isolated were 100% sensitive to imipenem followed by 96.2% sensitive to gentamicin and 95.3% to amikacin. CONCLUSIONS: Staphylococcus aureus (43%) was the most predominant isolate followed by Pseudomonas aeruginosa (23.4%), Proteus mirabilis (9.3%), and Escherichia coli (8.4%). Imipenem was the most sensitive antibiotic (100%) followed by gentamicin (96.2%), amikacin (95.3%), and ofloxacin (88.78%).

The impact of tensioning device mal-positioning on strand tension during anterior cruciate ligament reconstruction.

BACKGROUND: In order to confer optimal strength and stiffness to the graft in Anterior Cruciate Ligament (ACL) reconstruction, the maintenance of equal strand tension prior to fixation, is desired; positioning of the tensioning device can significantly affect strand tension This study aimed to determine the effect of tensioning device mal-positioning on individual strand tension in simulated cadaveric ACL reconstructions. METHODS: Twenty cadaveric specimens, comprising bovine tibia and tendon harvested from sheep, were used to simulate ACL reconstruction with a looped four-strand tendon graft. A proprietary tensioning device was used to tension the graft during tibial component fixation with graft tension recorded using load cells. The effects of the tensioning device at extreme angles, and in various locking states, was evaluated. RESULTS: Strand tension varied significantly when the tensioning device was held at extreme angles (p < 0.001) or in 'locked' configurations of the tensioning device (p < 0.046). Tendon position also produced significant effects (p < 0.016) on the resultant strand tension. CONCLUSION: An even distribution of tension among individual graft strands is obtained by maintaining the tensioning device in an unlocked state, aligned with the longitudinal axis of the tibial tunnel. If the maintenance of equal strand tension during tibial fixation of grafts is important, close attention must be paid to positioning of the tensioning device in order to optimize the resultant graft tension and, by implication, the strength and stiffness of the graft and ultimately, surgical outcome.