Computational Molecular Modeling Studies of Some Mycobacterium Tuberculosis Alanine Racemase Inhibitors

Alanine racemase is a pyridoxal-5′-phosphate dependent bacterial enzyme that provides the essential peptidoglycan precursor D-alanine, utilized for cell wall synthesis. This enzyme is ubiquitous throughout bacteria, including Mycobacterium tuberculosis, making it an attractive target for antibacterial drug discovery. We investigated the binding mode of twenty five reported Mycobacterium tuberculosis alanine racemase inhibitors. The results obtained from molecular docking studies emphasized the importance of inhibitor interaction with Lys42, Tyr46, Arg140, His172 and Tyr175 residues at the catalytic binding pocket of alanine racemase enzyme. The predicted binding free energies showed that van der Waals and nonpolar solvation interactions are the driving force for binding of inhibitors. Molecular dynamics simulation studies of four such inhibitor-alanine racemase systems were further explored to study the inhibition mechanism. The quantum chemical parameters calculated at the B3LYP/6-31G**++ level of theory indicated that the inhibitors must have low values of the lowest unoccupied molecular orbital energy and high values of electrostatic potential for stronger interactions. We expect that this study can provide significant theoretical guidance for design of potent Mycobacterium tuberculosis alanine racemase inhibitors in future

Patient’s Perception of Community Pharmacist in North Malabar region of Kerala, India: A questionnaire based study

Pharmacists as vital healthcare professionals play significant role in effective medication management and their use among the patients. However the perception of community pharmacist  among the public needs to be assessed for effective role and further patient care. This questionnaire based study was aimed to identify the perception of patients towards the community pharmacist in north Malabar region of Kerala, India. The questionnaire consisted of 16 questions with sections evaluating the demographic details (age, sex, marital status, education level & occupation) and the perception of patients towards the community pharmacist. The results were prepared based upon the responses obtained from 110 patients. The study respondents consisted of 51 (46.36%) adults (18-59 years) and 59 (53.63%) geriatrics (above 60 years). Based on their education level, 9 (8.18%), 35 (31.81%) and 66 (60%) participants were illiterate, secondary school and graduate holders respectively. The respondents of the study informed that the pharmacist enquired about their past medication history (58, 52.73%), any allergic reactions (21, 19.1%) and use of any herbal medication (31, 28.18%) prior to the dispensing process. The patients also responded that proper advice regarding dosage (90%), side effects (25%), storage (12%), healthy eating & exercise (10%) were also provided by the concerned pharmacist. As a matter of fact, 91 out of 110 patients thought the pharmacist service were good, 17 thought they were fairly good and 2 were of the opinion that it was poor. The pharmacy rating was evaluated as good by 32 (29.09%), fairly good by 78 (70.90%) and no respondents were of opinion that the pharmacy was poor in its service. Through this study, we found that the overall perception of patients towards the pharmacist in concerned community pharmacy setting was good. To further improvise their role, continued pharmacy education programmes, better communication skills and good professional training must be imparted among the community pharmacists

Mutantelec: AnIn Silicomutation simulation platform for comparative electrostatic potential profiling of proteins

The electrostatic potential plays a key role in many biological processes like determining the affinity of a ligand to a given protein target, and they are responsible for the catalytic activity of many enzymes. Understanding the effect that amino acid mutations will have on the electrostatic potential of a protein, will allow a thorough understanding of which residues are the most important in a protein. MutantElec, is a friendly web application for in silico generation of site-directed mutagenesis of proteins and the comparison of electrostatic potential between the wild type protein and the mutant(s), based on the three-dimensional structure of the protein. The effect of the mutation is evaluated using different approach to the traditional surface map. MutantElec provides a graphical display of the results that allows the visualization of changes occurring at close distance from the mutation and thus uncovers the local and global impact of a specific chang

Induced fit docking, free energy calculation and molecular dynamics studies on <i>Mycobacterium tuberculosis</i> alanine racemase inhibitor

<p>Alar, a Pyridoxal 5′-phosphate (PLP)-dependent bacterial enzyme is responsible for the racemisation of L-alanine into D-alanine which is essential for the peptidoglycan biosynthesis in both Gram-positive and Gram-negative bacteria. In the present study, we performed induced fit docking, binding free energy calculation and molecular dynamics simulation to elucidate the Alar inhibition potential of 1,2,4-thiadiazolidine-3,5-dione-based inhibitor <b>1</b>. The inhibitor binds to the hydrophobic groove of Alar and the binding was found to be stable throughout 20-ns MD simulation. Induced fit docking result showed that Lys42, Tyr46, Tyr175 and Tyr364 residues are primarily responsible for the stabilisation of inhibitor–protein complex. Further, high negative van der Waals binding free energy value of –38.88 kcal/mol, indicated it as the main driving force for the inhibitor binding. Based on the information obtained from this study, we designed few molecules as potent Alar inhibitor. In order to gain structural insight and to validate the stability of complex, we performed 20-ns MD simulation of the designed molecule <b>D1</b>. Results obtained from this study can be used for the design of <i>M. tuberculosis</i> Alar potent inhibitors lacking affinity for the co-factor PLP.</p