Structure based in silico virtual screening
- 1. Prepared by- Sandipan Choudhury 2nd semester, M.Pharm STRUCTURE BASED IN-SILICO VIRTUAL SCREENING PROTOCOLS
- 2. In silico: is a word used to mean experimentation performed by computer and is related to the more commonly known terms in vivo and in vitro. Virtual screening: uses computer based methods to discover new ligand on the bases of biological structure. The main goal of the virtual screening is the reduction of the enormous virtual chemical space of small organic molecules to synthesize and/or screen against a specific target protein, to a manageable number of the compound that inhibit the highest chance to lead to a drug candidate.
- 3. VIRTUAL SCREENING IN DRUG DESIGN
- 5. METHODS OF STRUCTURE BASED DRUG DESIGN Molecular docking: -Molecular docking helps to predict ligand-based receptor interaction -This method studies the binding mode and the position of the ligand in a protein’s binding site - Molecular docking has two main phases: (1) Sampling (2) Scoring
- 6. 1. Sampling: Geometry-based methods: divide the binding cavity and also the ligand to set of spheres. Then the software combines position of ligand-spheres and cavity-sphere Hash functions: transform information about ligand and receptor to a hash key. In the second recognition step, hash keys are matched and best combinations are evaluated
- 7. Incremental construction methods: are first algorithms that respect ligand flexibility. The software divides the ligand along each rotatable bond. Then the first fragment is placed and its best pose is the base for addition Genetic method: uses principles of evolutionary biology to locking for the best solution. It starts with zero generation of randomly created solutions. The next generations are created as combination of best-evaluated individuals from parent generation with some impact of random mutations.
- 8. Simulated annealing: is a part of molecular dynamic methods. The system is cooled during the simulation run, the energy is decreased and system is approaching the local minimum of energy. Using Monte Carlo algorithm particularly solves the dependence of the result on a starting position. It enables to overcome energetic barriers and to find global energetic minimum.
- 9. 2. SCORING Scoring is sometimes presented as a separate method of structure-based drug design but it is irreplaceable part of molecular docking. In the docking approaches, it is the second phase and it follows the sampling. There are three basic scoring methodologies based on different theories- 1. Force field scoring 2.Emperical scoring functions 3. Knowledge-based scoring functions
- 10. Force- field scoring functions:The force-field based scoring uses classical molecular mechanistic calculations. All these scoring functions have similar formulas based on sum of partial energies (bond interactions, van der Waals interactions, electrostatics interactions, angle bending, out-of-plane bending, torsion interactions and others)
- 11. Advantages: speed of computation strong physical basis and good theoretical description. Disadvantages: exclusion of the entropy parameters such as desolvation energy and restriction of ligand flexibility
- 12. Emperical scoring functions: Empirical scoring functions: calculate the binding energy as a sum of particular increments (e.g. ionic interactions, hydrogen bonds, π-interactions, desolvation, lipophilic interactions). Proportional weight of these increments is defined by their coefficients. Values of the coefficients are determined on training set of protein-ligand complexes using multiple linear regression
- 13. Advantage : The main advantage of this method is inclusion of enthalpy and entropy contribution. Disadvantage: Dependance on used training set.
- 14. Knowledge-based scoring functions: The third possibility is using of knowledge-based scoring functions. They are based on statistical investigation of protein-ligand complexes. The theory assumes that frequency of distance of two specific atom types is proportional to its favour. Partial increment of an atom- type pair can be calculated as:
- 15. where kB is the Boltzmann constant, T is the thermodynamic temperature, gij is the distribution function for atom-type pair ij and r is the distance between atoms i and j
- 16. Advantage: This method is relatively fast. Disadvantage: Poor physical theoretical-physical basis.
- 17. APPLICATIONS: Structure-based and in silico design of Hsp90 inhibitors:The molecular chaperone Hsp90 is responsible for activation and stabilization of several oncoproteins in cancer cells,and has emerged as an important target in cancer treatment because of this pivotal role .Interest have arisen around structure based design of small molecules aimed at inhibiting the chaperone activity of Hsp90. Hybrid Structure-Based Virtual Screening Protocol for the identification of Novel BACE1 Inhibitors.
- 18. Conclusions: The choice of a method is highly case dependent and there is no simple manual describing which method is the right one. Each method has its advantages or disadvantages. Combination of two or more computational methods is usually a favorable tool for drug design purposes It seems that it is possible to use VS methods in design of new drugs for military purposes including e.g. acetylcholinesterase or butyrylcholinesterase reactivators for antidotal treatment. In this case, the use of VS could help to develop molecules tailor-made for enzyme structure.
- 19. As such, a designed highly active reactivator could be applied for pseudocatalytic scavenging or treatment of intoxications caused by organophosphorus nerve agents.