Serine Proteinases from the Blood Coagulation Cascade

Schreuder, Herman; Matter, Hans

doi:10.1002/9781118681121.ch17

Cited by 6 publications

(10 citation statements)

References 168 publications

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“…It is essential to increase the positive charge on ring carbon atoms to augment the activity profile, which can be achieved by attaching electronegative atoms to the ring carbon atoms. This observation is in tune with previously reported studies [ 14 , 32 ], which highlighted that the aromatic cavity of the S4 pocket of factor Xa is suitable for positively charged lipophilic moieties. Thus, QSAR provides consensus results with reported crystal structures of inhibitors for factor Xa.…”

Section: Discussionsupporting

confidence: 93%

“…This observation is highlighted and supported by the presence of aroN_sp2C_4B in Apixaban. The X-ray-resolved structure of Apixaban with factor Xa confirmed that the pyrazole N2 nitrogen atom interacts with the backbone nitrogen atom of Gln192, whereas the carboxamide carbonyl makes a H-bond with NH of Gly216 [ 14 , 32 ]. Another example is Dabigatran (see Figure 4 ) [ 11 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The active site of factor Xa consists of a catalytic triad of His57, Asp102 and Ser195 in the heavy chain along with two subsites S1 and S4 (see Figure 6 ) [ 14 , 32 ]. The S1 sub pocket is approximately 8Å deep and encompasses Trp215-Gly216 on one side and Ala190, Cys191 and Gln192 on the other side.…”

Section: Discussionmentioning

confidence: 99%

“…In Figure 5, we have presented two examples, A and B, to understand the influence of fClamdN5B. The importance of fClamdN5B is vindicated by the fact that the NH of the chlorothiophene carboxamide of A is responsible for H-bond formation with Gly219 CO [14,32]. The molecular descriptor fsp2Osp3O6B stands for the frequency of occurrence of sp 3 -hybridized oxygen atoms exactly at six bonds from sp 2 -hybridized oxygen atoms.…”

Section: Mechanistic Interpretation Of Qsar Modelmentioning

confidence: 99%

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Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Zaki

Al‐Hussain

Masand³

et al. 2021

IJMS

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Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mechanistic Interpretation Of Qsar Modelmentioning

confidence: 99%

See 3 more Smart Citations

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Zaki

Al‐Hussain

Masand³

et al. 2021

IJMS

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Probing Factor Xa Protein–Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands

et al. 2022

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The accurate prediction of protein–ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen−π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

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Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach

Masand,

Al-Hussain,

Alzahrani

et al. 2024

Expert Opinion on Drug Discovery

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Serine Proteinases from the Blood Coagulation Cascade

Cited by 6 publications

References 168 publications

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Probing Factor Xa Protein–Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands

Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach

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