Exploring multi-target inhibitors using in silico approach targeting cell cycle dysregulator-CDK proteins.

Cyclin-dependent kinases (CDKs) belong to a family of multifunctional enzymes that control cell cycle modifications, transcription, and cell proliferation. Their dysfunctions result in different diseases like cancer making them an important drug target in oncology and beyond. The present study aims at identifying the selective inhibitors for ATP binding site in CDK proteins (CDK1, CDK2, CDK4, and CDK5) following a multi-target drug designing approach. Significant challenges lie in identifying the selective inhibitor for the ATP binding site as this region is highly conserved in all protein kinases. Molecular docking coupled with molecular dynamics simulation and free energy of binding calculations (MMPBSA/MMGBSA) were used to identify the potent competitive ATP binding site inhibitors. All the four proteins were docked against the library of drug-like compounds and the outcomes of the docking study were further analyzed by Molecular dynamics (total of 6µs) and MMPB/GBSA techniques. Five different inhibitors for structurally distant protein kinases, i.e. CDK1, CDK2, CDK4, and CDK5 are identified with the binding energy (ΔGbind-PB) in the range -18.24 to -28.43Kcal/mol. Mechanistic complexities associated with the binding of the inhibitor are unraveled by carefully analyzing the MD trajectories. It is observed that certain residues (Lys33, Asp127, Asp145, Tyr15, Gly16, Asn144) and regions are critical for the retention of inhibitors in active pocket, and significant conformational changes take place in the active site region as well as its neighbor following the entry of the ligand inside active pocket as inferred by RMSD and RMSF. It is observed that LIG3 and LIG4 are the best possible inhibitors as reflected from their high binding energy, interaction pattern, and their retention inside the active pocket. This study will facilitate the process of multi-target drug designing against CDK proteins and can be used in the development of potential therapeutics against different diseases.

Aetiology of tricuspid regurgitation.

BACKGROUND: Tricuspid regurgitation (TR) is regarded as a secondary disorder. Aim of the study was to know what percentage is secondary to heart and lung disease and its prevalence in normal adults. METHODS: Two hundred and 30 adults with clinically detectable TR were studied clinically to know the cause of TR. RESULTS: Thirteen percent of the adults were normal without any detectable cause for TR. In others, 24% of TR cases were secondary to ischemic heart disease (IHD) and hypertension was found in 14% cases. Sixteen percent had rheumatic heart disease (RHD) while chronic obstructive lung disease was found in 23% cases. The rest of 10% cases of TR had cardiomyopathy (CMP) and congenital heart disease as secondary causes. CONCLUSION: Ischemic heart disease, COPD and hypertension are common causes of TR. Others include RHD, CMP and congenital heart disease. Thirteen percent of apparently normal adults had TR.

Etiology of strokes and hemiplegia in children presenting at Ayub Teaching Hospital, Abbottabad.

BACKGROUND: Strokes in pediatric age group are not common. However diagnosing the cause of stroke will help in providing preventive and curative treatment. Present study was conducted to find etiology of strokes/hemiplegia in children. METHODS: This study was conducted in Department of Pediatrics, Ayub Teaching Hospital Abbottabad from December 2002 to December 2005. All children from two months to fifteen years of age were included in the study. Children with weakness due to acute poliomyelitis and Guillan barre syndrome were excluded. Investigations were based on findings on history and clinical examination and included full blood count, PT, APTT, Platelets count, ECG, Echocardiography, hematocrit, lumber puncture with CSF analysis and culture and CT-scan skull. Data of all the patients presenting with strokes/hemiplegia was entered on prepared proforma. RESULTS: The main etiology of strokes was intracranial infection causing strokes in 23(56.09%)children and majority of children (78.26%) in this group were below five years. Etiology was un-known in 7(17.07%) children after necessary available investigations. CONCLUSIONS: Intracranial infection Infections that is meningitis and encephalitis are commonest etiology of strokes and hemiplegia in paediatrics patients presenting at Ayub Teaching Hospital, Abbottabad.

Assessment of indoor radon doses received by the students in the Azad Kashmir schools, Pakistan.

Several epidemiological studies conducted on thousands of underground miners suggest that long- term exposure to high radon concentration can increase the risk of lung cancer. Keeping in view the importance of the subject, numerous studies throughout the world have been carried out to measure indoor radon concentration and its resulting doses at occupational and non-occupational sites. The purpose of the current study was to measure indoor radon concentration and its resulting doses received by the students of Azad Kashmir government schools. For this purpose, CR-39 radon detectors were installed in 80 carefully selected schools. The detectors were placed at a height of 3-5 ft. (depending upon average height of students in particular class) from the ground. After exposure of 90 d detectors were etched for 9 h in 6 M NaOH at 70°C and the observed track densities were related to radon concentrations. The measured indoor radon concentration ranged from 22 ± 9 to 228 ± 3 Bq m(-3) with a mean value of 78 ± 5 Bq m(-3). Based on the measured indoor radon data, the annual effective doses were found to vary from 0.55 ± 0.04 to 0.71 ± 0.03 mSv y(-1). The overall mean effective dose for the studied area was found to be 0.63 ± 0.04 mSv y(-1). Reported values for radon concentrations and corresponding doses are lower than ICRP recommended limits for workplaces.