Important Interaction in Drug Receptor Complex And Intro to De Novo Drug Design.pptx

#Important Interaction in Drug Receptor Complex And Intro to De Novo Drug Design
Its includes all the interaction like covalent and non covalent interaction like ionic (electrostatic) interactions,
ion-dipole and dipole-dipole interactions,
Hydrogen bonding,
Charge-transfer interactions,
Hydrophobic interactions,
Halogen bonding,
Vander Waals interactions. And introduction to de novo dug design which includes the procedure for LUDI Softwares and other vavity site prediction.

1. Presented by Yogesh Kailas Chaudhari M. Pharm Sem II Credit Seminar 2023-24 Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule Topic: Important Interaction (Forces) Involved In Drug Receptor Complex and Introduction to De Novo Drug Design Guided by Dr. Pawan Kumar Gupta (Associate Professor) Department of Pharmaceutical Chemistry

2. What is Drug Receptor Complex? The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response, i.e., a change in cell function. D + R D-R Drug Response

3. The structure of the 20 primary amino acids are given in figure. Amino acid are divided into hydrophobic and hydrophilic residues.

4. Important interaction (forces) involved in drug receptor complex. Interactions involved in the drug-receptor complex are the same forces experienced by all interacting organic molecules. Covalent bonding, ionic (electrostatic) interactions, ion-dipole and dipole-dipole interactions, Hydrogen bonding, Charge-transfer interactions, Hydrophobic interactions, Halogen bonding, Vander Waals interactions. These include:-

5. Covalent Bonds – Majority of the drug combine with their receptor by weak molecular interaction. These interaction forms a strong link between the drug and it’s receptor but individually the interaction are irreversible . It formed by a drug-receptor interaction, with enzymes and DNA. Example : The diuretics drug ethacrynic acid is an A,B - Unsaturated ketone, act by covalent bond formation with sulfhydryl groups of ion transport system in the renal tubules. Ethacrynic Acid

6. For covalent bond formation, there should be two poles; the electrophile and the nucleophile. Nucleophiles in biology have the following functional groups: Thiol in the amino acid cysteine. Hydroxyl in the amino acid serine. Amine in the amino acid lysine. Carboxylate in the amino acid glutamic acid Electrophiles Epoxide ring. Alkyl group attached to halogen. Positively charged centre.

7. 2. Ionic (or Electrostatic) Interactions Drug and receptor groups will be mutually attracted provided they have opposite charges. This ionic interaction can be effective at distances farther than those required for other types of interactions, and they can persist longer. Basic groups such as the amino side chains of arginine, lysine are protonated and, therefore, provide a cationic environment. Acidic groups, such as the carboxylic acid side chains of aspartic acid and glutamic acid, are deprotonated to give anionic groups. Arginine

8. 3. Ion-Dipole and Dipole-Dipole Interactions Greater electronegativity of atoms such as oxygen, nitrogen, sulphur, and halogens relative to that of carbon, will have an asymmetric distribution of electrons; this produces electronic dipoles. These dipoles in a drug molecule can be attracted by ions (ion-dipole interaction) or by other dipoles (dipole-dipole interaction) in the receptor, provided charges of opposite sign are properly aligned. Dipole-Dipole interaction > ion-dipole interaction.

9. 4. Hydrogen Bonds Hydrogen bonds are a type of dipole-dipole interaction formed between the proton of a group X-H, where X is an electronegative atom, and one or more other electronegative atoms (Y) containing a pair of non-bonded electrons. X removes electron density from the hydrogen so it has a partial positive charge, which is strongly attracted to the non-bonded electrons of Y. The interaction is denoted as a dotted line, -X-H---Y-.

10. 5. Charge-Transfer Complexes When a molecule that is a good electron donor comes into contact with a molecule that is a good electron acceptor, the donor may transfer some of its charge to the acceptor. This forms a charge-transfer complex.

11. 6.Halogen Bonding Covalently bonded halogen atom can act as an electron acceptor (Lewis acid) to undergo halogen bonding with an electron-rich donor atom, such as O, N, or S. The strength of these interactions is in the order H=I>Br> Cl >>F.

12. 7. Vander Waals or London Dispersion Forces Atoms in nonpolar molecules may have a temporary non- symmetrical distribution of electron density, which results in the generation of a temporary dipole . Consequently , intermolecular attractions, known as van der Waals forces, result.

13. De Novo Drug Design De novo means start a fresh , from the beginning from the scratch. 3D structure of receptor used to design newer molecules. It involves structural determination of the lead target complex and lead modification using molecular modelling tools. Ligand optimization can be done by analysing protein active site properties that could be probable area of contact by the ligand . Structure of the binding site can be identified from x-ray crystallography study of the target protein containing ligand or inhibitor. The analysed active site properties are described to negative image of the protein such as: Hydrogen bond donor, Hydrogen bond acceptor, Hydrophobic contact region.

14. Principle In de novo design, the structure of the target should be known to a high resolution and the binding to site must be well defined. This should define not only a shape constrain (refers to the specific 3D structure or conformation that the receptor protein must adopt in order to properly bind to its ligand ( molecule that binds to the receptor ) but hypothetical interaction sites, typically consisting of hydrogen bonds, electrostatic and other non-covalent interactions. Firstly it assembles all possible compounds and evaluating their quality which is enable searching the sample space for novel structures with drug like properties.

15. The first type of method has been described as outside in method in which the binding site is first analyzed to determine where specific functional groups might bind tightly. These groups are connected together to give molecular skeletons, which are then converted into ' real ' molecules. In the inside out method molecules are grown within the binding site, under the control of an appropriate search algorithm on the basis of energy function. In this study flexible molecules are better than rigid molecules. Fig. De Novo Drug Design T wo basics types of de novo design algorithms :

16. Types Of De Novo Drug Design Manual Design It is slow. A single novel structure. Automated Design It is much faster. Large number diverse structures. Procedure For De novo Drug Design:- Crystallize target protein with Bound ligand (enzyme+ ligand). Acquire Structure By X-ray crystallography. Identify Blinding site.

17. 4. Identify potential binding region in the Binding site. 5. Design a lead compound to interact with the Binding site. 6. Synthesis the lead compound and test it for activity. 7. crystallize the lead compound with target protein and Identify the actual Binding Interaction.

18. Important Points To Take Consideration In De Novo Drug Design. Flexible molecule are better than rigid molecule because the earlier have more likely to find the alternative binding conformation should they fail to bind as expected. If the rigid molecule fails to bind as predicted, it may not bind to all. It is pointless designing molecule which are difficult or impossible to synthesize . Similarly it is pointless designing molecules which need to adopt an unstable conformation in order to bind.

19. Software used in De novo drug design

20. Several computer software program have been which are automatically design novel structure to fit known binding sites. The following are some examples. LUDI – One of the best known de novo software program is called LUDI. Which works by fitting molecular fragments to different regions of the binding site, then linking the fragments together.

21. Interaction Site For ex - binding site contain methyl group. Program will identify the carbon of that group as an aliphatic carbon capable of taking part in Vander Waal interaction. Identification of Interaction Sites Fitting Molecular Fragments T ypically 5-30 atoms in size Fragment bridging Synthesis the lead compound Other software – SPROUT , LEGAND.

22. APPLICATIONS Design of HIV 1 protease inhibitors Design of bradykinin receptor antagonist Catechol ortho methyl transferase inhibitor Ex.entacapone and nitecapone Estrogen receptor antagonist Purine nucleoside phosphorylase inhibitors

23. References: Wang M, Wang Z, Sun H, Wang J, Shen C, Weng G, Chai X, Li H, Cao D, Hou T. Deep learning approaches for de novo drug design: An overview. Current opinion in structural biology. 2022 Feb 1;72:135-44 . Medina JR, Blackledge CW, Heerding DA, Campobasso N, Ward P, Briand J, Wright L, Axten JM. Aminoindazole PDK1 inhibitors: a case study in fragment-based drug discovery. ACS medicinal chemistry letters. 2010 Nov 11;1(8):439-42. Schneider G, Fechner U. Computer-based de novo design of drug-like molecules. Nature Reviews Drug Discovery. 2005 Aug 1;4(8):649-63. Silverman RB, Holladay MW. The organic chemistry of drug design and drug action. Academic press; 2014 Mar 29.