Basic Concepts in Medicinal Chemistry

Harrold, Marc W.; Zavod, Robin M.

doi:10.3109/03639045.2013.789908

Cited by 34 publications

(30 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While ketones and aldehydes are rarely present in drug molecules [186], they are functional groups that occur in acyclic carbohydrates in biological systems. The Drude polarizable force field for aliphatic ketones and aldehydes (e.g.…”

Section: Current Status Of Drude Polarizable Force Field For Small Ormentioning

confidence: 99%

Force Fields for Small Molecules

Lin

MacKerell

2019

Methods in Molecular Biology

View full text Add to dashboard Cite

Summary Molecular dynamics (MD) simulations have been widely applied to computer-aided drug design (CADD). While MD has been used in a variety of applications, such as free energy perturbation and long-time simulations, the accuracy of the results from those methods depends strongly on the force field used. Force fields for small molecules are crucial as they not only serve as building blocks for developing force fields for larger biomolecules but also act as model compounds that will be transferred to ligands used in CADD. Currently, a wide range of small molecule force fields based on additive or non-polarizable models have been developed. While these non-polarizable force fields can produce reasonable estimations of physical properties and have shown success in a variety of systems, there is still room for improvements due to inherent limitations in these models including the lack of an electronic polarization response. For this reason, incorporating polarization effects into the energy function underlying a force field is believed to be an important step forward, giving rise to the development of polarizable force fields. Recent simulations of biological systems have indicated that polarizable force fields are able to provide a better physical representation of intermolecular interactions and, in many cases, better agreement with experimental properties than non-polarizable, additive force fields. Therefore, this chapter focuses on the development of small molecule force fields with emphasis on polarizable models. It begins with a brief introduction on the importance of small molecule force fields and their evolution from additive to polarizable force fields. Emphasis is placed on the additive CHARMM General Force Field and the polarizable force field based on the classical Drude oscillator. The theory for the Drude polarizable force field and results for small molecules are presented showing their improvements over the additive model. The potential importance of polarization for their application in a wide range of biological systems including CADD is then discussed.

show abstract

Section: Current Status Of Drude Polarizable Force Field For Small Ormentioning

confidence: 99%

Force Fields for Small Molecules

Lin

MacKerell

2019

Methods in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…In the above context, it would be worthwhile to investigate the effect of another halo group at position 6’ ( Figure 19 ) on the conformation locking of the aromatic rings in analogy with the NSAID pair, fenoprofen/diclofenac. In diclofenac ( Figure 21 ), the two ortho -positioned chloro groups resulted in a restricted conformation with consequent enhanced selectivity, efficacy, and potency compared to fenoprofen, in which the two chloro groups are absent [ 76 ].…”

Section: Aromatic Hydroxy (Arenolic) Metabolitesmentioning

confidence: 99%

“…Diclofenac is a phenylacetic acid NSAID. It was developed as a variant of fenoprofen by introducing two ortho -positioned chloro groups in the anilino-aromatic ring to restrict its free rotation [ 76 ]. This restriction of rotation increases selectivity, and hence, potency with respect to fenoprofen.…”

Section: Aromatic Hydroxy (Arenolic) Metabolitesmentioning

confidence: 99%

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

et al. 2018

View full text Add to dashboard Cite

Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development.

show abstract

“…In diclofenac (Fig. 2.5), the two ortho-positioned chloro groups have resulted in a restricted conformation with consequent enhanced selectivity, efficacy, and potency compared to fenoprofen, in which the two chloro groups are absent [74].…”

Section: Benzodiazepines: Diazepam and Estazolam The Benzodiazepinesmentioning

confidence: 99%

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

El‐Haj¹,

Ahmed²,

Qarawi³

et al. 2018

Preprint

View full text Add to dashboard Cite

Drug functionalization through formation of hydrophilic groups is the norm in phase I metabolism of drugs for modification of drug action. The reactions involved are mainly oxidative catalyzed mostly by CYP isoenzymes. The benzene ring, as phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e. the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e. the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retaining, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues have been presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design and drug development.

show abstract

Basic Concepts in Medicinal Chemistry

Cited by 34 publications

References 0 publications

Force Fields for Small Molecules

Force Fields for Small Molecules

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

Contact Info

Product

Resources

About