Aug
12
Mon
2013
Plenary Talk: Watching the network change during the formation of associative memory @ Amriteshwari Hall
Aug 12 @ 9:27 am – 9:58 am

UpinderUpinder S. Bhalla, Ph.D.
Professor & Dean, NCBS, Bengaluru, India


Watching the network change during the formation of associative memory

The process of learning is measured through behavioural changes, but it is of enormous interest to understand its cellular and network basis. We used 2-photon imaging of hippocampal CA1 pyramidal neuron activity in mice to monitor such changes during the acquisition of a trace conditioning task. One of the questions in such learning is how the network retains a trace of a brief conditioned stimulus (a sound), until the arrival of a delayed unconditioned stimulus (a puff of air to the eye). During learning, the mice learn to blink when the tone is presented, well before the arrival of the air puff.

The mice learnt this task in 20-50 trials. We observed that in this time-frame the cells in the network changed the time of their peak activity, such that their firing times tiled the interval between sound and air puff. Thus the cells seem to form a relay of activity. We also observed an evolution in functional connectivity in the network, as measured by groupings of correlated cells. These groupings were stable till the learning protocol commenced, and then changed. Thus we have been able to observe two aspects of network learning: changes in activity (relay firing), and changes in connectivity (correlation groups).

Upi Bhalla Upi

Aug
13
Tue
2013
Invited Talk: Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery @ Sathyam Hall
Aug 13 @ 2:15 pm – 2:40 pm

lalithaLalitha Subramanian, Ph.D.
Chief Scientific Officer & VP, Services at Scienomics, USA


Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery

Lalitha Subramanian, Dora Spyriouni, Andreas Bick, Sabine Schweizer, and Xenophon Krokidis Scienomics

The discovery of a compound which is potent in activity against a target is a major milestone in Pharmaceutical and Biotech industry. However, a potent compound is only effective as a therapeutic agent when it can be administered such that the optimal quantity is transported to the site of action at an optimal rate. The active pharmaceutical ingredient (API) has to be tested for its physicochemical properties before the appropriate dosage form and formulation can be designed. Some of the commonly evaluated parameters are crystal forms and polymorphs, solubility, dissolution behavior, stability, partition coefficient, water sorption behavior, surface properties, particle size and shape, etc. Pharmaceutical development teams face the challenge of quickly and efficiently determining a number of properties with small quantities of the expensive candidate compounds. Recently the trend has been to screen these properties as early as possible and often the candidate compounds are not available in sufficient quantities. Increasingly, these teams are leveraging nanoscale simulations similar to those employed by drug discovery teams for several decades. Nanoscale simulations are used to predict the behavior using very little experimental data and only if this is promising further experiments are done. Another aspect where nanoscale simulations are being used in drug development and drug delivery is to get insights into the behavior of the system so that process failures can be remediated and formulation performance can be improved. Thus, the predictive screening and the in-depth understanding leads to experimental efficiency resulting in far-reaching business impacts.

With specific examples, this talk will focus on the different types of nanoscale simulations used to predict properties of the API in excipients and also provide insight into system behavior as a function of shelf life, temperature, mechanical stress, etc.

Delegate Talk: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors @ Sathyam Hall
Aug 13 @ 3:55 pm – 4:10 pm
Delegate Talk: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors @ Sathyam Hall | Vallikavu | Kerala | India

Rajasekhar Chekkara, Venkata Reddy Gorla and Sobha Rani Tenkayala


Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors

Polo-like kinase 1 (PLK1) is a significant enzyme with diverse biological actions in cell cycle progression, specifically mitosis. Suppression of PLK1 activity by small molecule inhibitors has been shown to inhibit cancer, being BI 2536 one of the most potent active inhibitor of PLK1 mechanism. Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 54 compounds belonging to Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK1 inhibitors. A six-point pharmacophoremodel AAADDR, with three hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R) was developed by Phase module of Schrdinger suite Maestro 9. The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (r2 = 0.88, SD = 0.21, F = 57.7, N = 44) and for test set (Q2 = 0.51, RMSE = 0.41, PearsonR = 0.79, N = 10). The original set of compounds were docked into the binding site of PLK1 using Glide and the active residues of the binding site were analyzed. The most active compound H18 interacted with active residues Leu 59, Cys133 (glide score = −10.07) and in comparison of BI 2536, which interacted with active residues Leu 59, Cys133 (glide score = −10.02). The 3D-QSAR model suggests that hydrophobic and electron-withdrawing groups are essential for PLK1 inhibitory activity. The docking results describes the hydrogen bond interactions with active residues of these compounds. These results which may support in the design and development of novel PLK1 inhibitors.