molecular interactions and conformations

Question 1

SAR and pharmacophore

Answer 1

structure activity relationship - relationship between chemical structure of drug and biological activity, pharmacophore - 3D ensemble of steric and electronic features of a molecule necessary to ensure optimal molecular interactions with specific biological target structure in order to bind with sufficient affinity to activate/block biological response

Question 2

Hund rule

Answer 2

each p orbital must be filled with one electron before they will begin to pair up

Question 3

molecular orbitals - hydrogen

Answer 3

2 x 1s atomic orbitals form 2 molecular orbitals sigma and sigma*, shared electrons fill lower energy sigma

Question 4

molecular orbitals - methane

Answer 4

outer shell of carbon has 2 electrons in the 2s orbital and 1 electron in each of the 2/3 of its 3 2p orbitals, in order to share 4 electrons carbon forms 4 degenerate (same energy) hybrid sp3 orbitals, tetrahedral arrangement of sp3 orbitals of carbon can interact with 4 x 1s orbitals from hydrogen to form methane, sp3 and 1s orbitals merge to form atomic orbitals, methane consequently has perfect tetrahedra arrangement of bonds

Question 5

sp3 hybrid orbitals

Answer 5

4 hybrid sp3 orbitals are formed from 1 x s and 3 x p atomic orbitals

Question 6

molecular orbitals ammonia

Answer 6

outer shell of nitrogen has 2 electrons in 2s and 1 electron in all of the 3 2p orbitals, unlike carbon one of the sp3 orbitals already have 2 electrons, not available for bonding , other 3 are tho (bond with 3 hydrogens)

Question 7

molecular orbitals - water

Answer 7

outer shell of oxygen has 2 electrons in its 2s orbitals and 2 electrons in one of its 2p orbitals and 1 electron in its other 2 2p orbitals, 2 of the sp3 orbitals already have 2 electrons so not available for bonding, other two are (bond with hydrogen)

Question 8

pre-filled sp3 orbitals

Answer 8

result in lone pairs of electrons, closer to central atom compared to shared electrons in the bond, push the bond electrons away so bonds become closer together, result in bond angle less than 109.5 degrees (ammonia - 107, water - 104.5

Question 9

molecular orbitals - ethane

Answer 9

as we build up to more complex molecules same rules apply, all bond angles of ethane are approximately 109.5 and there are only sigma bonds, sigma bonds can rotate, 3 hydrogens on each carbon in ethane spin like helicopter as central bond rotates

Question 10

molecular orbitals - ethene

Answer 10

1 x s orbital only hybridises with 2 x p orbitals to give 3 sp2 hybrid orbitals, 1 p orbital remains unchanged, 3 sp2 orbitals arranged in plane and separated by 120 degrees, hence ethene is planar, sp2 orbitals can form sigma bonds with another carbon sp2 and also 1s orbitals of hydrogen to form m molecular orbitals, however still 2 x p orbitals (one on each carbon) with only one electron in, these overlap to for pi bond (only one pi bond - electron cloud partially above and partially below sigma bond - electrons are part wave part particle, easier to imagine them as a cloud that has an over-all charge of -1 but can shift about)

Question 11

molecular orbitals - benzene

Answer 11

aromatic rings are special case when considering single/double bonds, simplest example benzene has its pi electrons in 3 double bonds shared across all six bonds in the ring, delocalisation, aromatic rings common in drug structures, flat planar structures

Question 12

molecular orbitals - naphthalene

Answer 12

pi electrons in naphthalene delocalised across 2 aromatic rings

Question 13

molecular orbitals - formaldehyde

Answer 13

formaldehyde is a central carbon atom with a double bonded oxygen and two hydrogens, combination of common biological elements, follows similar pattern to ethene except oxygen has two lone pair rather than 2 sigma bond to hydrogen (carbon and the oxygen are both sp2), 2 x C-H sigma bonds, 1 x C-O sigma bond, 1 x C-O pi bond

Question 14

molecular orbitals - amides

Answer 14

a regular 2p orbital (not hybridised) on nitrogen containing lone pair of electrons, next door is pi bond between carbon and oxygen, lone pair on nitrogen can interact with pi orbital of carbonyl group (delocalisation)

Question 15

molecular orbitals - ethyne

Answer 15

sp (only 2 hybrid sp orbitals other 2 p orbitals remain unchanged) orbitals are 180 degrees apart, one bonds with neighbouring carbon and other with hydrogen, however still 4 x p orbitals (2 on each carbon) with only one electron in each, overlap to form two pi bonds (triple bonded carbons each bonded to one hydrogen)

Question 16

molecular conformations - ethane

Answer 16

bond angles approximately 109.5, only sigma bonds, all single covalent bonds bonds can spin, doesn’t have any affect for C-H bond, when C-C bond in ethane spins position of hydrogens change (each half of the molecule as propeller)

Question 17

dihedral angles (torsion angles)

Answer 17

Newman projection is way of defining rotation about a single bond, can define the conformation around that bond using the dihedral angle (portion angle), staggered theta = 60 degrees, eclipse theta = 0 degrees

Question 18

molecular conformations - butane

Answer 18

3 C-C bonds number of different conformations increases, imagine looking down central C-C bond - as central bond rotates the methyl group at one end of molecule moves closer/further from hydrogens and methyl group at opposite end, energy is highest when two terminal methyl groups are closest, also high when there is clash between terminal methane and terminal hydrogen, molecule prefers to be in one of the 3 lowest energy conformations also referred to as rotomers (anti and gauche), is a choice of conformation for each single bond, also so restraint (side chains of all amino acids in a protein - conformation of each single bond in side chain follows these rules, likewise single bonds in drug molecule also follows the rules)

Question 19

geometric isomers - 2-butene

Answer 19

inability of double bon ds to rotate means there can be two distinct geometric isomers - trans and cis conformation, major implications to conformation of drug

Question 20

ring closure - single bonds unable to rotate

Answer 20

ring systems with single bonded carbons found in ligands, simplest version of such ring is cyclohexane - not planar like benzene, is puckered and can form chair or boat conformation, often find oxygen or nitrogen inserted into this puckered ring system (glucose), informs us possible to prevent single bond rotation by inserting ring system, chair conformation moist stable

Question 21

isomers via ring closure

Answer 21

if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms) cis/trans stereoisomerism is possible, if more than two ring carbons have substituents stereo-chemical notion distinguishing various isomers becomes more complex and prefixes cis/trans cannot be used to formally name the molecule

Question 22

stereoisomers around tetrahedral carbons

Answer 22

any sp3 carbon that has 4 different groups attached to its chiral centre has two possible stereoisomers (optical isomers/enantiomers), stereoisomers are molecules with the same molecular formula, atom connectivity but differ in relative spatial orientation of the atoms

Question 23

ring closure - muscarine

Answer 23

shape molecule adopts critical for biological action, acetylcholine activates muscarinic and nicotinic receptors, however muscarine an analogue of ACh which shares pharmacophoric features but is conformationally locked by insertion of ring structure then this only activates muscarinic receptors, muscarine mimics conformation of ACh when it binds to muscarinic receptor but must be different to conformation adapted when binding to nicotinic receptor

Question 24

single bonds - delocalised pi electrons

Answer 24

not all single bonds can rotate due to delocalised pi electrons - gives double bond character (e.g. peptide bond in protein main chain does not rotate due to amide group - has partial double bond character due to delocalisation of electrons, usually fixed in trans conformation, as amide groups are planar conformational flexibility of peptide main chain limited to rotation round the other two bonds, 3 main conformations for each bond but final conformation depends upon global stability of protein fold as whole), also used in drug design - migration of bond, conformational restriction

Question 25

hydroxyl group

Answer 25

uncharged in organic compounds, doesn’t ironise to form hydroxide ion, polar and can form hydrogen bonds, make important drug target interactions

Question 26

carbonyl group

Answer 26

carbon with double bonded oxygen then two other groups - carbon atom of carbonyl group is at centre of planar arrangement of its 3 neighbours, C=O is polar so oxygen can accept hydrogen bond

Question 26

carbonyl group

Answer 26

carbon atom of carbonyl group is at centre of planar arrangement of its 3 neighbours, C=O is polar so oxygen can accept hydrogen bond

Question 27

carboxyl group

Answer 27

carbon with double bonded oxygen, hydroxide group and another group - can ionise to release proton so is acidic (carboxylic acid), negative charge at physiological pH, p orbitals overlap across carbon and both oxygens (which are in the same plane) so the pi bond and negative charge is delocalised

Question 28

amino/amine group

Answer 28

nitrogen bound to 3 groups (primary - 2 hydrogens and 1 other group, secondary - 1 hydrogen and 2 other groups, tertiary - no hydrogens, all other groups) - polar, can form hydrogen bonds, can bind protons such that nitrogen atom becomes positively charged (quaternary amine - positively charged, acetylcholine)

Question 29

amide group

Answer 29

carbon atom with double bonded oxygen and NH2 group bound with another group bound - doesn’t not ionise, are polar can form hydrogen bonds, the 2 hydrogens can be replaced with other groups

Question 30

drug design - in silico benefits

Answer 30

cost - 100000’s compounds screened, speed - 1000s/day (set up dependant), no assays - high throughput screening dependant on a readout assay, mutations - can be screened easily by changing search model

Question 31

drug development - in silico downsides

Answer 31

reliability - results always with caveats, many false positives and negatives, structure - needs to be known, dynamics - not easy to model dynamics of the system, isolation - done in isolation of other cellular factors

Question 32

basis of In silco drug design

Answer 32

first factor - shape complamentarity, hand in glove analogy where small molecule fits well in pocket

Question 33

hydrophobic interactions

Answer 33

many interactions are hydrophobic and include Van Der Waal interactions, although each is weak the number of these makes it a significant interaction

Question 34

hydrogen bonding

Answer 34

attractive forces between water molecules is a dipole interaction, hydrogen atoms are bound to a highly electronegative oxygen atom (also has 2 lone pairs making for a very polar bond, partially positive hydrogen atom of one molecule is then attracted to oxygen atom of nearby water molecule)

Question 35

electrostatic interactions

Answer 35

electrostatics are when complementary charges can attract and form a tight interaction

Question 36

covalent bonds

Answer 36

very string and aid in protein folding and stability, using this chemistry helps develop small molecules that also covalently bind and therefore are very tight binders

Question 37

in silico uses

Answer 37

predict binding site of inhibitor, design new inhibitor, modify inhibitor to improve potency/mitigate mutations or avoid patents, identify new chemical scaffold from thousands of compounds

Question 38

fragment design

Answer 38

in silico used to design small molecules that bind different pockets, then computationally stitched together and tested to generate a new potent inhibitor

Question 39

ranking hits

Answer 39

one of biggest challenges is ranking hits and selecting good from bad, need biological assay

Question 40

bioinformatics - benefits

Answer 40

quick, large range of tools available, often inexpensive

Question 41

bioinformatics - disadvantages

Answer 41

based on models, can produce large amounts of data, predictions often need to be validated and always right

Question 42

editing secondary structure - ‘basic rules’

Answer 42

methionine, alanine, leucine, glutamate and lysine (MALEK) have strong propensity to form a helix, however proline and glycine not as common, for beta sheets large aromatics (tyrosine, phenylalanine, tryptophan) and smaller branched (threonine, valine, isoleucine), these rules can break down tho

Question 43

homology modelling on previous structures

Answer 43

by taking sequence you can predict structure based on already solved structures or secondary structure prediction, however families of proteins that have not had their structures solved are hard to. model as templates not available

Question 44

protein-protein interactions

Answer 44

important process in cell life cycle, by blocking these we can design therapeutics to manipulate cellular processes, challenging as surface of protein often hard to target due to ‘flatness’

Question 45

protein-protein interaction (PPI) inhibitors

Answer 45

by targeting the surface you can inhibit protein-protein interaction and therefore inhibit pathway, alternatively you can stop regulator and therefore increase specific pathways

Question 46

amyloid PPI inhibitors

Answer 46

for amyloid growth its been shown small molecule such as ADH-41 stops polymerisation, often small molecules mimic alpha helices with compounds that mimic side chains

Question 47

multiple sequence alignments

Answer 47

sequence conservation provides important information as there is evolutionary pressure to maintain them (region important for catalysis, regulation, protein folding and protein/protein interactions), for inhibitor design sequence conservation info is important for - identifying good target sites for small molecule intervention, show areas that could be easily mutated/inhibitor resistance, look for related proteins/motifs, well conserved regions can often indicate active site of protein and important areas that can be targeted by small molecule intervention

Question 48

post translational modifications

Answer 48

cells have sophisticated system of modifications that can be used to target and regulate protein function (phosphorylation, ubiquitination, glycosylation, lipidation/prenylation)

Question 49

phosphorylation

Answer 49

can trigger conformational changes of protein, carried out by kinases, over 130000 predicted sites for phosphorylation, commonly done on Ser, Thr ad Tyr residues

Question 50

ubiquitination

Answer 50

addition of ubiquitin, allows control of proteins fate, can determine localisation or degradation, protein targeting for degradation can be used in therapy

Question 51

glycosylation

Answer 51

commonly on Ser, Thr, Tyr, Asp or Arg residues, can be used to aid in folding and stability/ cell-to-cell adhesion, allows for greater diversity of proteome, plays key role in immune system and diseases such as cancer progression

Question 52

expression test

Answer 52

if we have a target we need to know how often and where its expressed , allows us to maximise potency, also use this approach to see proteins that or over/under expressed in particular disease state, look at expression patterns in different environmental conditions

Question 53

data mining

Answer 53

data can be used to examine geographical spread