S . VENKATESH III/IV B . PHARMACY CIPS , LAM , GUNTUR .

History of Drug Discovery Early 19th century - extraction of compounds from plants (morphine, cocaine).

Late 19th century - fewer natural products used, more synthetic substances. Dye and chemical companies start research labs and discover medical applications. (Bayer) 1905 - John Langley: Theory of receptive substances which stated The concept of specific receptors that bind drugs or transmitter substances onto the cell, thereby either initiating biological effects or inhibiting cellular functions

1909 - First rational drug design. Goal: safer syphilis treatment than Atoxyl.Paul Erhlich and Sacachiro Hata wanted to maximize therapeutic index . Synthetic: 600 compounds; evaluated ratio of minimum curative dose and maximum tolerated dose. They found Salvarsan (which was replaced by penicillin in the 1940s)

1960 - First successful attempt to relate chemical structure to biological action quantitatively.

Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to influence a drugs activity, stability, etc.

Discovery and Development The time from conception to approval of a new drug is typically 10-15 years. The estimated cost to bring to market a successful drug is now $800 million! 20% cost increase per year.

How drugs are discovered? Mainly by accident

Can be discovered by

screening of new drugs modification for improvement mechanistic based drug design combining techniques

Life Cylce of Drug Design Traditional Life Cycle

Modern drug design

Find a Lead CompoundExisting drugsNatural substrate or productCombinatorial synthesis Computer-aided designX-ray crystallography of binding sitesMolecular modeling to design drug

Introduction to CADDComputer Aided drug design lies In the hand of computational scientists, who are able to manipulate molecule on the screen Rather it is a complex process involving many scientist from various stream working together.

Molecular mechanicsormolecular dynamicsDrug design with the help of computers may be used at any of the following stages of drug discovery:hit identification usingvirtual screening(structure- or ligand-based design)hit-to-leadoptimization of affinity and selectivity (structure-based design,QSAR, etc.)lead optimizationoptimization of other pharmaceutical properties while maintaining affinity.

CADD (Approaches) : Strucuture BasedCrystal Strucuture AnalysisHomolgy ModelingComputional Analysis of Protien Lignad InteractionModification of Ligand within the Active Site for Better DesignLignad BasedQSARLead IdentificationIn-Silico solubility, BBB & Toxicity PredictionLead OptimizationPreclinical Trail

Target Based Drug Design Structure KnownStructure UnknownActive Site AnalysisLigand Binding Model via DockingLigand ModificationIdentify Template & Build ModelModel Validation & OptimizationReceptor Based Search in 3DNew Scaffold database searchcombiLibSynthesis

Ligand Based Drug Discovery Ligand activites knownQualitative property informationoptimizationDescriptor calculationGenerate conformerFeature genreationPharmacophore hypothesis3D database searchNew scaffold2D databaseCombiLib with new ScaffoldQSARAlignment2D QSARCombiLibScreening of LibrarySynthesis

Objective of CADDTo change from:Random screening against disease assaysNatural products, synthetic chemicals

To:Rational drug design and testingSpeed-up screening process Efficient screening (focused, target directed)De novo design (target directed) Integration of testing into design process Fail drugs fast (remove hopeless ones as early as possible)

Principles Governing CADD

Molecular Mechanics Quantum Mechanics

Molecular mechanicsMolecular mechanics refers to the use of classical mechanics to model the geometry and motions of molecules. Molecular mechanics methods are based on the following principles: 1)Nuclei and electrons are lumped into atom-like particles. 2)Atom-like particles are spherical (radii obtained from measurements or theory) and have a net charge (obtained from theory). 3)Interactions are based on springs and classical potentials. 4)Interactions must be preassigned to specific sets of atoms. 5) Interactions determine the spatial distribution of atom-like particles and their energies.

The object of molecular mechanics is to predict the energy associated with a given conformation of a molecule.A simple molecular mechanics energy equation is given by:Energy = Stretching Energy + Bending Energy +Torsion Energy + Non-Bonded Interaction Energy

Quantum mechanicsQuantum theory uses well known physical constants ,such as velocity of light, values for the masses & charges of nuclear particles to calcaulate molecular properties The equation from which molecular properties can be derived from schrodinger equation H=E

Quantum theory is based on Schrodinger's equation:

H=EFull wave functionElectron wave function E-energy of the system relative to all atomic particles are separated to infinite distances H-is the Hamiltonian operator which includes both kinetic and potential energy

What is Docking?

Docking attempts to find the best matching between two molecules

It includes finding the Right Key for the Lock

Given two biological molecules determine:

Whether the two molecules interactIf so, what is the orientation that maximizes the interaction while minimizing the total energy of the complex

Goal: To be able to search a database of molecular structures and retrieve all molecules that can interact with the query structure

Docking Protocol

What Are Docking & Scoring?To place a ligand (small molecule) into the binding site of a receptor in the manners appropriate for optimal interactions with a receptor.To evaluate the ligand-receptor interactions in a way that may discriminate the experimentally observed mode from others and estimate the binding affinity. ligandreceptorcomplexdockingscoring etcX-ray structure& DG

Why Do We Do ?To Reduce costCore of the target-based structure-based drug design (SBDD) for lead generation and optimization.

Three Components of Docking Representation of receptor binding site and ligand pre- and/or during docking:Sampling of configuration space of the ligand-receptor complexduring docking:Evaluation of ligand-receptor interactionsduring docking and scoring:

Types of Docking Studies Protien Ligand StudiesFlexible Ligand, Rigid Receptor Search much Larger Space Search the conformational Space using Molecular Dynamic Protien- Protien Docking Both Molecule Usually Considered Rigid 6 Degree of freedom 1st aplly stearic Constrains to limits search Space & then examine Energetic of Possible Binding Conformation.

ApplicationsDetermine the lowest free energy structures for the receptor-ligand complexSearch database and rank hits for lead generation Calculate the differential binding of a ligand to two different macromolecular receptorsStudy the geometry of a particular complexPropose modification of a lead molecules to optimize potency or other propertiesde novo design for lead generationLibrary design

Successes of Docking & SBDDHIV protease inhibitor amprenavir (Agenerase) from Vertex & GSK (Kim et al. 1995) HIV: nelfinavir (Viracept) by Pfizer (& Agouron) (Greer et al. 1994)Influenza neuraminidase inhibitor zanamivir (Relenza) by GSK (Schindler 2000).

Docking:

Program nameWeb siteArgusDockwww.Arguslab.comDOCKhttps://dock.compbio.uscsf.eduFREDwww.eyesopen.comeHITSwww.symbiosys.ca/Autodockwww.scripps.eduFTDockwww.bmm.icnet.uk/docking/ftdock.html

Future Challenges For DockingBetter Scoring Functions High-Throughput Screening Tractable Models of FlexibilityThe so-called computational molecular docking problem is far from being solved. There are two major bottle-necks:

The algorithms can handle only a limited extent of backbone flexibilityThe availability of selective and efficient scoring functions

Advantages of CADD Time cost Accuracy information about the disease screening is reduced Database screening less manpower is required

Future trends or Advances Shape signatures Inverse docking

Success stories of CADD K+ ion channel blocker structural based discovery G. Schneider et al., J. Computer-Aided Mol. Design 14, 487-494, 2000

Ca2+ antagonist / T-channel blocker chemical descriptor based discovery G. Schneider et al., Angew. Chem. Int. Ed. Engl. 39, 4130-4133, 2000

Glyceraldehyde-phosphate DH inhibitors (anti-trypanosomatid drugs) combinatorial docking J.C. Bressi et al., J. Med. Chem. 44, 2080-2093, 2001

Thrombin inhibitor docking, de-novo design H.J. Bohm et al., J. Computer-Aided Mol. Design 13, 51-56, 1999

Aldose reductase inhibitors database searching Y. Iwata et al., J. Med. Chem. 44, 1718-1728, 2001

Non nucleoside inhibiitor of HIV-1 reverse Transcriptase structure and ligand based design William L. Jorgensen et al., bioorganic and midicinal chemistry letters, 16, 663-667, 2006

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