Applications of molecular modeling

Aplications of Molecular ModellingBy:

Abhideep Dey BBI-III-13004Shivani Khodidas BBI-III-13007Ashwini Mushunuri BBI-III-13010Vinit kale BBI-III-13015

INDEX

1) Direct Drug Design2) Indirect Drug Design3) Molecular Mimicry4) Tools & Trades of molecular modelling

Molecular modeling in Direct Drug Design

Abhideep Dey BBI-III-13004

Introduction

In the direct approach, the three-dimensional features of the known receptor site are determined from X-ray crystallography to design a lead molecule.

In direct design, the receptor site geometry is known; the problem is to find a molecule that satisfies some geometric constraints and is also a good chemical match. After finding good candidates according to these criteria, a docking step with energy minimization can be used to predict binding strength.

Molecular Modeling Applications

The starting point for many computer assisted molecular modeling studies is generally a two-dimensional drawing of a required molecule. These diagrams can range from note-book sketches to electronically stored connection tables in which one defines the types of atoms in the molecule, their hybridization and how they are bonded to each other. Then the two-dimensional structures are transformed into three-dimensional representations to study chemical properties. However, more accurate molecular structures may be available from the Cambridge X-ray crystallographic database (about 50,000 structures). Various applications of computer assisted molecular modeling techniques are reviewed here.

Generation of Chemical Structures

Molecular structures may be generated by a variety of software. The 3D structures of molecules may be created by several common building functions like make-bond, break-bond, fuserings, delete-atom, add-atom-hydrogens, invest chiral center, etc. Computer modeling allows chemists to build dynamic Models of compounds which in turn allows them to visualize moleculargeometry and demonstrate chemical principles.

Generation of Conformations

The most active area of theoretical research using molecular orbital theory has been in the prediction of the preferred conformation of molecules. Most molecules exist in multiple conformations. The preferred conformation of a molecule is a structural characteristic feature that arises as a response to the Force of attraction and repulsion. The shape should be considered primarily in determining the interaction of the molecule with the receptor. The minimization energy is a function of bond angles, bond lengths, torsion angles and non-covalent interactions. By varying these parameters in a systematic way and calculating the total energy as a sum of orbital energies, one can determine a minimum energy structure for example, by using conjugated gradient algorithm working under universal force field.

Docking (Molecular Interactions)

Modeling the interaction of a drug with its receptor is a complex problem. Many forces are involved in the intermolecular association: hydrophobic, dispersion, or van der Waals, hydrogen bonding, and electrostatic. The major force for binding appears to be hydrophobic interactions, but the specificity of the binding appears to be controlled by hydrogen bonding and electrostatic interactions. Modeling the intermolecular interactions in a ligand-protein complex is difficult because there are so many degrees of freedom and insufficient knowledge of the effect of solvent on the binding association.

Determination of Molecular Properties

Molecular properties are important indicators of various chemical molecules including pharmaceuticals. Molecular properties are normally categorized as physical, chemical and biological. The three major computational methods used for calculation of properties of molecules are: 1)Empirical (molecular mechanics): Molecular mechanics methods are less complicated, fast, and are able to handle very large systems including enzymes.

2)Molecular dynamics: Molecular dynamics simulations have been used in a variety of bimolecular applications.

3)Quantum mechanics: Quantum mechanics is one of the oldest mathematical formalisms of theoretical chemistry.

Determination of Drug Excipient Interactions

Molecular modeling technique became popular to study the drug-excipient interaction which helps to visualize the type and site of interaction on a computer monitor. It was reported in a study that seven glucose units were combined to get a well shaped energy minimized conformation. The cavity depth, diameter of a wider and narrower rim were calculated and compared to the literature values using DTMM package. Similarly, norfloxacin, ciprofloxacin, etc. structures were built to get energy minimized conformation. The dimensions of these molecules were measured and compared to literature values. The drug molecules were allowed to penetrate through the cavity and the probability of penetration was observed. Finally, the success in the formation of inclusion complex of betacyclodextrin with norfloxacin, ciprofloxacin, tinidazole and methotrexate was reported.

Lead Generation

A lead is any chemical compound which shows biological activity. It is not the same as a drug molecule, but its generation is an important step in drug discovery process. It is the process of identifying potential drug compounds or Leads that interact with a target with sufficient potency and selectivity. Lead generation is a complex process, which involves two basic steps:

i) Lead finding: Here the task is to find a chemical compound,which has a desired biological activity.

ii) Lead optimization: Lead optimization involves elaboratingaround the basic lead structure to build in all the desirableproperties, such as safety, solubility, etc.

Determination of Properties of Pharmacophoric Pattern

A pharmacophoric pattern may be defined as geometrically arranged functionality possessed by a set of active compounds having some mechanism of action. Identification of pharmacophores is specially useful for designing receptor agonists and antagonists, enzyme inhibitors, etc. Molecular modeling approach has been particularly rewarding indopamine agonists, antagonists and for drugs acting on histamine and morphine receptors.

ConclusionsMolecular modeling, an inexpensive, safe

and easy to use tool, helps in investigating, interpreting, explaining and identification of molecular properties using three-dimensional structures. Since different models yield different results, it is necessary to have a small number of standard models which are applicable to very large systems.

Molecular modelling in Indirect Drug Design

(aka Ligand based drug design)

Vinit Kale BBI-III-13015

Ligand

• A ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex.

• Ligand selection is a critical consideration in many practical areas, including bioinorganic and medicinal chemistry, homogeneous catalysis, and environmental chemistry.

Stratergies in IdDd

• The Appropriate strategy to use in the design of drugs depends on available knowledge about the structure of the macromolecular target.

Indirect drug designing aka Ligand based drug designing: • It relies on knowledge of other molecules that bind to the biological target of interest • These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must posses in order to bind to the target.

PHARMACOPHORE

•Pharmacophore model:–Set of points in space defining the binding of

ligands with target.–Key factors in developing such a model are

the determination of functional groups essential for binding, their correspondence from one ligand to another, and the common spatial arrangement of these groups when bound to the receptor.

PHARMACOPHORE

• “A molecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological activity” Paul Erlich, early 1990.• “a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule’s activity” Peter Gund, 1977.

Other techniquesQuantitative Structure-Activity Relationships (QSAR)

• A QSAR relates a numerical description of molecular structure or properties to known biological activity:– Activity = f (molecular descriptors)– Success of QSAR: right descriptors + right

method (form of f )


• A QSAR should be:– explanatory (for structures with activity data)– predictive (for structures without activity data)

• A QSAR can be used to explain or optimise:– localised properties of molecules such as binding

properties– whole molecule properties such as uptake and

distribution• Correlate general properties of molecules with their biological activities


• The earliest examples of QSAR were Hansch analysis and Free-Wilson Analysis,

• Free-Wilson defined a function that equates activity (defined as log of 1 / the concentration) with weighted descriptors, the weightings, or coefficients, being determined by linear regression. That is, we have the equation:

Log (1/C) = a1x1 + a2x2 + a3x3 ...

where C is the concentration required for activity, x1, x2, x3, etc are the descriptor values (usually 1 or 0 to represent absence or presence of features), and a1, a2, a3, etc are the coefficients derived from linear regression.

Molecular Mimicry in Molecular Modelling

Shivani Khodidas BBI-III-13007

Key Terms

• Homology• Epitome• Endogenous• Domain• Conformation• Autoimmune response

Molecular Mimicry

Molecular mimicry is similar structures shared by molecules from dissimilar genes or by their protein products.

Mimicing molecules can share linear amino acid sequences or conformational shapes, even with separate origins.

Microbes may have chemical structures that mimic host proteins.

The molecules may be close enough in homology (between self and microbe) to share determinants or distant enough from homology to be recognized as foreign to the immune system.

Molecular Mimicry

• Microbe and Host Cell:– Share of a linear amino

acid sequence ;– Share of conformation fit.

• Host immune response against the microbe reacts if the host sequence comprises a biologically important domain.

• Autoimmunity may occur.

How does it work?

The criteria for molecular mimicry in the pathogenesis of disease is usually: (1) linear or conformational homology of a peptide

between an agent and a host-antigen; (2) cellular and/or antibody-mediated immune

response with the homologous peptide;(3) immune response in patients without disease; (4) immune response results in organ-specific damage;(5) organ specific damage results in disease.

How does it work?

• Host develops an immune response to an agent that cross-reacts with a host antigen which results in autoimmune disease.

• Structural mimicry, rather than sequence mimicry, is more common.

• Molecular mimicry plays significant role in:– Guillain-Barr Syndrome (GBS);– Myasthenia gravis (MG);– Epilepsy;– Celiac disease;– Antiphospholipid syndrome (APS);

Auto-Immune Disease

Molecular mimicry is a mechanism that can initiate immuno-reactivity leading to autoimmune disease via a shared immunologic epitope with a microbe and the host.

• When molecular mimicry induces autoimmune diseases, an adjuvant is required.

• Prime challenge model:– Virus mimicking a host CNS protein can prime animals for disease

induced by a different virus infection later in life;– Virus primes T cells, but not to the point where they can initiate

autoimmune inflammatory CNS disease;– Later events may trigger these cells to cause disease.

• Viruses that have molecular mimicry with host proteins may be used as vaccines to prevent autoimmune disease later in life.

Human Immunodeficiency Virus (HIV)

Human cytomegalovirus (HCMV)

HCMV can mimic a cell’s regulatory protein to overtake a cell’s growth machinery. This regulatory protein is the cell's primary anti-cancer mechanism.

• Dupes hosts cell to grow and spread.• Mimics a regulatory protein to hijack a healthy cell’s growth machinery

and disrupts primary anti-cancer mechanism.

• Virus protein UL97:– Mimics regulatory enzyme that controls tumor-suppressing protein;– Lacks on/off trigger to control growth;

However, uncontrolled cell proliferation though HCMV can lead to cancer and other disorders. One of the most important cellular control mechanisms works through a protein called the retinoblastoma tumor suppressor protein, which slows cell growth.

EspFU

Some pathogens target their host cytoskeleton. This assists with pathogen attachment, entry, and cell-to-cell spreading.

Enterohaemorrhagic E. coli causes severe gastrointestinal disease. Its infection requires attachment to the epithelial cells in the intestine via actin pedestals. These pedestals are formed by the pathogen protein EspFU which stimulates actin polymerization by activating the host’s WASP family proteins.

EspFU

a: EspFU is secreted from E. Coli into a host cell where it stimulates actin polymerization through N-WASP and ARP2/3, leading to pedestal formation.

b: N-WASP is inhibited, but can be activated by inputs such as CDC42.

c: Multiple activators are necessary to potently activate N-WASP.

d: EspFU potently activates N-WASP via in vitro pyrene-actin-polymerization assay.

Battling mimics like the Poxviruses

• Many pathogens use mimicry to subvert cellular processes: – Cell cycle ;– Apoptosis ;– Cytoskeletal dynamics1;– Immunity;

• Although pathogens gain advantages by mimicking cellular components– PKR competes in a molecular ‘arms races’

with mimics ;– Evolutionary flexibility;

• Figure: single substitutions in either the aE or aG helices produces resistance.

TOOLS & TRADES OF MOLECULAR MODELLING

Ashwini Mushunuri BBI-III-13010

Introduction

Molecular modelling is a tool for doing chemistry & it is a skill demanding science. Modelling is easy to perform with currently available tools.

The tools & trade have gradually evolved form physical models & calculators to most recently integrated internet based tools & work benches based on HTML, JavaScript etc.

The following are used for modelling of a drug through computer:

Hardware for graphics & modelling

a. Central servers: The Central Server provides the necessary functionality for handling event information, node management and performance monitoring. No matter how many nodes are registered in the cluster, from the user's point of view Central provides an efficient and useful single point of entrance.

Hardware for graphics & modelling

b. High performance graphic system: The real time of manipulation of representation of macromolecules require specialized graphics hardware to draw many tens or thousands of objects with depth cueing, stereo & high line quality necessary for full 3D perception of molecules.

c. Personal workstations: A workstation is a special computer designed for technical or scientific applications. Intended primarily to be used by one person at a time, they are commonly connected to a local area network and run multi-user operating systems

Software Components of Molecular Graphics & Modeling system

a. User Inter face : All modern software are presented to the user through some bewildering verity of user interface techniques. These include control panel, icons, side bars etc. The function of all these is to make software more accessible to the scientist & easy to use.

b. Constructing initial model: There are two distinct methods for generating an initial model for molecular system


• The model can either be derived from existing structural information in database or the chemical intelligence of the user & molecular modelling system can be used to generate model within the system.

• A wide range of techniques are available for generating initial model which includes:

i. Entering 1D notation from which a rule based approach can produce 3D structure.

ii. Sketching a 2D diagram of the structure either generated free hand or by connecting fragments.

iii. Building model in 3D similar to 2D


c. Refining the model : Once an initial model of a molecular model has been constructed, it is necessary to explore the confirmations available to the molecule. Sometimes the lowest energy structure of a molecule of interest.

d. Manipulating the model : The essence of interactive modelling system is the ability of the scientist to explore the confirmation variability & properties of molecules & how they may interact with each other. In most molecular modeling system there is a need of some basic modeling tools such as: Moving molecules or fragments of molecules Solid docking procedures. Semi automated docking procedures. Specification of flexible bonds & rotation around torsion angles of a molecule


e. Visualization :It briefly reviews the illustrates the different techniques available for display of molecular structure & properties. The simplest & mostly widely used graphical method for representing them is vector graphics where the bonds in the molecules are represented as line joining atoms.

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Applications of molecular modeling

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