Pharmacology and toxicology

(PHA C332_2014)
Onkar Kulkarni
Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Pain pathway
Nature. 1994 Jan 20;367(6460):243-9.
The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.
Picot D
1
, Loll PJ, Garavito RM.
Author information
1
Department of Biochemistry and Molecular Biology, University of Chicago, Illinois
60637.
Abstract
The three-dimensional structure of prostaglandin H2 synthase-1, an integral membrane
protein, has been determined at 3.5 A resolution by X-ray crystallography. This
bifunctional enzyme comprises three independent folding units: an epidermal growth
factor domain, a membrane-binding motif and an enzymatic domain. Two adjacent but
spatially distinct active sites were found for its haem-dependent peroxidase and
cyclooxygenase activities. The cyclooxygenase active site is created by a long,
hydrophobic channel that is the site of non-steroidal anti-inflammatory drug binding.
The conformation of the membrane-binding motif strongly suggests that the enzyme
integrates into only one leaflet of the lipid bilayer and is thus a monotopic membrane
protein.
Rheumatology (Oxford). 1999 May;38 Suppl 1:14-8.
Molecular model of the interaction between nimesulide and human cyclooxygenase-2.
Garca-Nieto R
1
, Prez C, Checa A, Gago F.
Author information
1
Departamento de Farmacologa, Universidad de Alcal, Madrid, Spain.
Abstract
The cyclooxygenase-2 (COX-2) isoenzyme is a key target for COX-2-selective non-steroidal
anti-inflammatory drugs (NSAIDs). An important difference in binding of nimesulide
compared with non-selective NSAIDs appears to involve the amino acid at position 523
of the enzyme. Replacement of valine with isoleucine at this position provides access to
a binding site that is larger in COX-2 than in COX-1. Nimesulide appears to exploit this
enlarged binding site for establishing a number of favourable contacts with the enzyme
that lead to selective inhibition of COX-2. We made these conclusions from a three-
dimensional molecular model of the active site of human COX-2, constructed using the
X-ray coordinates of COX-1 from sheep seminal vesicles and COX-2 from mouse
fibroblasts as templates, with the aid of sequence alignment methods and molecular
modelling techniques. The resulting model was refined, and the active site was probed
for regions of steric and electrostatic complementarity for ligand binding. Docking
studies were then undertaken with many different nimesulide conformers, a family of
which could establish very favourable interactions with the NSAID binding site of human
COX-2 by exploiting the extra space made available by the isoleucine/valine
replacement. The stability of the resulting complexes was studied by simulating
molecular dynamics.
Med Chem. 2007 Mar;3(2):127-34.
2-Amino/azido/hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines:
synthesis and pharmacological evaluation.
Bruno O
1
, Brullo C, Bondavalli F, Ranise A, Schenone S, Tognolini M, Ballabeni V,
Barocelli E.
Author information
1
Dipartimento di Scienze Farmaceutiche, Universit degli Studi di Genova, Viale
Benedetto XV, 3-16132 Genova, Italy. obruno@unige.it
Abstract
New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the
chemical modulation of the substituent in position 2 of the scaffold, with the aim to
produce analgesic/antiphlogistic agents more potent than analogues previously
reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing
test; the analgesic doses of the compounds did not affect mice spontaneous
locomotor activity thus any confounding sedative effect could be excluded. These
derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced
platelet aggregation, probably due to a strong, non selective, inhibition of
cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the
compounds did not cause gastric damage in rats after acute oral administration. A
different pharmacological profile was observed for the 2-azido derivatives,
particularly in vivo
Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Identify the disease pathomechanism
Various organs affected and their specific
roles
Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Molecules and various factors involved
in the disease progression
Structural identification of various
molecules

Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Identify chemical moieties binding
specifically to the target molecule

Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Proof of concept studies with novel molecules
Animal studies to evaluate the efficacy
Cell culture and animal studies to determine
pharmacokinetic pattern
Cell culture and animal studies to determine
unwanted effects

Patho-physiology
Drug discovery
Molecular biology
Medicinal Chemistry
Pharmacology
Toxicology
Clinical Studies
Evaluation of pharmacokinetic and safety
profile in humans
Efficacy and safety in humans
Efficacy and benefit over existing drugs in the
market
Post marketing surveillance
Lect. No. Learning Objectives Topics to be covered Section no. of Text
book
1-2
General Pharmacology Introduction, Scope and important terms of
Pharmacology and Toxicology
I
3-4
Mechanisms of drug action
5-6
Introduction to Pharmacokinetics
7-9
Pharmacodynamics
10-11
Drugs acting on ANS Introduction to nervous system II
12-14
Cholinergic drugs and cholinergic blockers
15-17
Adrenergic drugs and their blockers
18-20
Ganglionic and Neuromuscular blockers
21
Drugs acting on CNS Introduction VII
22-24
General and Local anesthetics
25-27
Anxiolytic, sedatives and hypnotics
28-30
Antipsychotic and antidepressants
31-33
CNS stimulants and anticonvulsants
34-37
Neurodegenerative diseases, Anti-Parkinson agents
38-41
Autacoids Autacoids and antihistaminic drugs III
Lect. No. Learning Objectives Topics to be covered
1-2
General Pharmacology Introduction, Scope and important terms of Pharmacology and
Toxicology
3-4
Mechanisms of drug action
5-6
Introduction to Pharmacokinetics
7-9
Pharmacodynamics
Learning objectives

Drug-receptor interaction, types of receptor, receptor downstream pathways
Importance of Pka, various parameters of Pka
Drug response curve, quantitative parameters of drug action
10-11
Drugs acting on ANS Introduction to nervous system
12-14
Cholinergic drugs and cholinergic blockers
15-17
Adrenergic drugs and their blockers
18-20
Ganglionic and Neuromuscular blockers
Learning objectives

Anatomy of nervous system
Anatomy and physiology of ANS
Cholinergic neurotransmission, drug acting on cholinergic system
Adrenergic neurotransmission, drug acting on adrenergic system
21
Drugs acting on CNS Introduction
22-24
General and Local anesthetics
25-27
Anxiolytic, sedatives and hypnotics
28-30
Antipsychotic and antidepressants
31-33
CNS stimulants and anticonvulsants
34-37
Neurodegenerative diseases, Anti-Parkinson agents
38-41
Autacoids Autacoids and antihistaminic drugs
Learning objectives

Anatomy of nervous system
Anatomy and physiology of ANS
Cholinergic neurotransmission, drug acting on cholinergic system
Adrenergic neurotransmission, drug acting on adrenergic system