Characteristics and Prevalence of Latent Autoimmune Diabetes in Adults (LADA)

Diabetes, one of the most commonly seen metabolic disorders, is affecting a major area of population in many developing as well as most of the developed countries and is becoming an alarming concern for the rising cost of the healthcare system. Latent Autoimmune Diabetes in Adults (LADA) is a form of diabetes which is less recognized and underdiagnosed type of diabetes which appears to have characteristics of both type 1 (autoimmune in nature) and type 2 diabetes (adult age at onset and initial response to oral hypoglycemic agents). An epidemiological study was carried out on 500 patients in the western region of India. Various parameters such as age at onset, duration of diabetes, gender, basal metabolic index (BMI), type of diabetes, family history, HbA1c levels, cholesterol levels, and current treatment regimen were evaluated and correlated with type 1 and type 2 diabetes. Moreover, diagnostic markers for LADA, namely, GAD autoantibodies and C-peptide levels, were determined for 80 patients selected from the epidemiological study. Some of the results obtained were found to be consistent with the literature whereas some results were found to be contradictory to the existing data

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R(2) = 0.49). However, the addition of the active-site waters resulted in significant improvement (R(2) = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors