MEDC 607 & MEDC 603 1 Lead Series IND IND Full Toolbox Required to Compete Successfully Rational Drug Discovery Biological Discovery High Volume Screening Combinatorial Diversity Rational [Structure, Design, Informatics] Lead Discovery Research Iterative Process Biodisposition Toxicity Efficacy Pharmacokinetics Preclinical R&D
Lead Series
Feb 07, 2016
Biological Discovery. Biodisposition. High Volume Screening. Toxicity. IND. Lead Series. Combinatorial Diversity. Efficacy. Rational [Structure, Design, Informatics]. Pharmacokinetics. Iterative Process. Preclinical R&D. Lead Discovery Research. Rational Drug Discovery. - PowerPoint PPT Presentation
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MEDC 607 & MEDC 603 1
Lead Series INDIND
Full Toolbox Required to Compete Successfully
Rational Drug Discovery
Biological Discovery
High VolumeScreening
CombinatorialDiversity
Rational[Structure, Design,
Informatics]
Lead DiscoveryResearch
IterativeProcess
Biodisposition
Toxicity
Efficacy
Pharmacokinetics
PreclinicalR&D
MEDC 607 & MEDC 603 2
Rational Drug Discovery
Definition
Types of Drug Discovery Searches
Rational – Reason-based Not based on chance alone May not involve computers
Structure – based Drug Design(structure of the receptor, binding site, AA residues, thermodynamics)
Pharmacophore – based Drug Design (structure of the ligand, SAR, QSAR)
Mechanism – based Drug Design(molecular mechanism of action, transition state)
MEDC 607 & MEDC 603 3
helix D
helix P
RCL
helix A
A) B)
Lys136
Arg133
Lys132
Arg129
Lys125
Arg47
Arg46
Lys114
D
EF
G
H
EHBS
PBS
helix D
helix P
RCL
helix A
A) B)
Lys136
Arg133
Lys132
Arg129
Lys125
Arg47
Arg46
Lys114
D
EF
G
H
helix D
helix P
RCL
helix A
A) B)
Lys136
Arg133
Lys132
Arg129
Lys125
Arg47
Arg46
Lys114
D
EF
G
H
EHBS
PBS
Receptor-based Drug Design
Design of Antithrombin Activators
MEDC 607 & MEDC 603 4
O
OH
OH
O
COO
O
O
CH2OSO3
NHSO3
OSO3
O
O
CH2OSO3
NHSO3
OH
O
OSO3
OH
O
COOO
O
CH2OSO3
NHSO3
OH
_ _ _ _
_ _
_ _ _ _
Arg129Lys125 Lys114
Arg46Arg47
Lys11Arg13Asn45
Receptor-based Drug Design
Binding Site Information
MEDC 607 & MEDC 603 5
0
1
2
3
4
5
Lys11 Arg13 Asn45 Arg46 Arg47 Lys114 Lys125 Arg129
G
O (k
cal/m
ol)
Receptor-based Drug Design
Thermodynamics
MEDC 607 & MEDC 603 6
Receptor-based Drug Design
Computerized Modeling
MEDC 607 & MEDC 603 7
A) B)
O
OSO3
OSO3
OSO3
OSO3
O3SO_
_
_
_
_
O
OSO3
OSO3
R
O3SO
O3SO
O
R'
_
_
_
_
ECS = (2S,3S)(+)CS = (2S,3R)
MoS :: R = H, R’ = OSO3-
QS :: R = OSO3-, R’ = H
23
0
1000
2000
3000
4000
5000
6000
7000
Lys11 Asn45 Arg47 Lys114 Lys125 Arg129 Total
Pentasaccharide Binding Site Residues
HIN
T Sc
ore
DEF =ECS =
Receptor-based Drug Design
Design of New Structures
MEDC 607 & MEDC 603 8
O OR'
OR
CH3 N
Morphine R = R’ = HCodeine R = Me, R’ = HHeroin R = R’ = COCH3
(Analgesic + additive)
OH
OH
CH3 N
OH
Levorphanol(a morphinan)
(3 – 4X morphine analgesic + retains additive property)
CH3CH3
OH
CH3 N
Pentazocine
(less potent than morphine+ reduced additive property)
OH
CH3 N
(less potent than morphine+ reduced additive property)
CH3 NO
OEt
Meperidine
(10-12% of morphine analgesic+ much lowered additive)
Methadone
(equipotent as morphine analgesic+ almost no additive)
CH3
CH3 N Ph
CH2CH3
O
Pharmacophore-based Drug Design
Natural Product Derivatization and Pharmacophore Elucidation
MEDC 607 & MEDC 603 9
O
O
O
O
H
HO
H
R' NH
R
O
O
OH
H O
O
OH
R' NH
R
O
O
O
O
O
O
R' NR
O
HH
H
H
O
O
O
O
O
R'
O
H
H
NR
H
H
O
O
O
O
HO
O
O
O
H
HO
H
Mechanism of Aspartic Proteinases
_
_ _
_
+
___
Mechanism-based Drug Design
Design of HIV Protease Inhibitor
MEDC 607 & MEDC 603 10
NNH
OH
COO-tBu
PhCH2O
O
Z.Phe[CH(OH)CH2N]Pro.OtBu 6,500
Inhibitor Structure HIV-1 HIV-2IC50 (nM)
NNH
COO-tBuO
NH
CH2CONH2
O
PhCH2OOH
Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu 140 330
NNH
COO-tBuO
NH
CH2CONH2
O
PhCH2OOH
Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu 300
Mechanism-based Drug Design
MEDC 607 & MEDC 603 11
Inhibitor Structure HIV-1 HIV-2IC50 (nM)
NNH
O
NH
CH2CONH2OH
O
CH2CH(CH3)2
NH
O
PhCH2O
NHO
CH(CH3)CH2CH3
CONH-iBu
Z.Leu.Asn.Phe[CH(OH)CH2N]Pro.Ile.NHiBu 750
NNH
CONH-iBuO
NH
CH2CONH2
O
PhCH2OOH
Z.Asn.Phe[CH(OH)CH2N]Pro.NHiBu 210
NNH
O
NH
CH2CONH2
O
PhCH2OOH
CONH-iBu
Z.Asn.Phe[CH(OH)CH2N]PIC.NHiBu 18
Rational Design of HIV-1/2 Proteinase Inhibitors
MEDC 607 & MEDC 603 12
N
NNH
O
NH
CH2CONH2OH
CONH-iBu
O
QC.Asn.Phe[CH(OH)CH2N]PIC.NHiBu 2 9.5
N
NNH
O
NH
CH2CONH2OH
O
CONH-iBu
QC.Asn.Phe[CH(OH)CH2N]DIQ.NHiBu <0.4 <0.8
Inhibitor Structure HIV-1 HIV-2IC50 (nM)
Rational Design of HIV-1/2 Proteinase Inhibitors
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