Q1 . (a) Many proteins from pathogens have human homologues. Suppose you had a m

Question

Q1.

(a) Many proteins from pathogens have human homologues. Suppose you had a method for
comparing the determinants of specificity in the binding sites of two homologous proteins. How could
you use this method to select relevant targets for drug design?

(b) Choose one example where the
principles of computer aided drug design (CADD) have been specifically used for the design and
discovery of a drug that is currently in active and widespread use. You should be as specific as feasible
in the way CADD was used in the discovery and development of the selected drug.

Q2.

(a) What should molecular properties of a small molecule drug be such that its ADME parameters
transports it efficiently across the blood brain barrier? Give examples of the drugs that have these
structural properties (e.g. active transporters)

(b) Use principles of molecular modeling and drug
design to explain the mechanisms of how enzymes evolve new functions.

(c) How is the Buckingham
potential a more realistic one compared to the Lennard Jones potential in modeling VDW interactions
in proteins and nucleic acids? Write out the potential energy expression using the Buckingham
potential. Define and explain its adjustable parameters.

(d) How would you combine a MC and a MD
algorithm to perform a molecular simulation on a biological system.

Q3.

(a) What are the differences between an energy based ligand design method such as GRID and a
knowledge based one like LUDI? What are the requirements of a knowledge based ligand design
method?

(b) Interpret the following QSAR equation: log (1/C)=k 1 ?-k 2 ? 2 + k 3 ?. How are factorial design
methods using in QSAR compound selection? Briefly outline how multiple linear regression analysis is
used in the derivation of a QSAR equation. How is cross-validation used for checking the quality of a
regression based QSAR model?

Q4.

(a) Use the example of molecular docking of the antibiotic netropsin to DNA to distinguish
quantitatively the differences between steepest descent and conjugate gradient methods for initial
refinement and stringent minimization. What qualitative conclusions can be drawn about the efficacy
of these two minimization techniques with respect to this docking experiment?

(b) Using two
examples, explain the thermodynamic differences between the Molecular Dynamics and Monte Carlo
methods. What are the advantages to choosing periodic boundary conditions in ANY molecular
simulation of a macromolecule? Use a diagram to plot 4 such periodic cell shapes. What important
class of applied molecular simulations have benefitted from the usage of periodic boundary
conditions?

Explanation / Answer

Answer 1:

Part a) It is widely observed that many pathogens share protein sequence and structural similarity with their human hosts. This information is used to design novel drugs against these pathogens. Bioinformatics and in silico applications have made it possible to design novel molecules which can bind either to the pathogen protein or the protein/receptor on the human host and thus prevent their mutual interaction. This lack of interaction between the two leads to failure of the pathogen to survive in the host cell/human cell by either preventing its entry or causing its rapid clearance from the cells. Thus, these novel molecules are promising therapeutic agents.

Part b) Global research is being conducted for designinig in silico drug molecules which can be used as therapeutic interventions. In this regard, surface receptor VEGF blockers have gained special importance. The VEGF play role in multiple tumorigenesis processes and leads to onset and spreading of cancer in the body. Studies have shown that multiple receptor blockers and antagonists were designed against this receptors, out of which only 1 or 2 emerged out to have physiological benefits, hence are used in their chemical analogue forms as anti-cancerous drugs.

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