New inhibitor quadrupole mutant PfDHFR as antimalaria candidate: Structure-based pharmacophore, molecular docking, ADMET, molecular dynamic, and chemical quantum study

Putra Jiwamurwa Pama Tjitda; Febri Odel Nitbani

Makale detayları

New inhibitor quadrupole mutant PfDHFR as antimalaria candidate: Structure-based pharmacophore, molecular docking, ADMET, molecular dynamic, and chemical quantum study

Yazarlar:

Putra Jiwamurwa Pama Tjitda | Febri Odel Nitbani

Yayıncı:

Marmara University

Ana Başlıklar:

Pharmacology and Pharmaceutical Sciences (Other)

Dergi:

Journal of Research in Pharmacy Vol.29 Issue 2, pp.790-805

Belge Tipi:

Makale

Yayın Tarihi:

8/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001341724

pISSN:

2630-6344

Anahtar kelimeler:

Özet:

 Genetic mutations in the dihydrofolate reductase-thymidylate synthase PfDHFR-TS enzyme of the malaria parasite Plasmodium falciparum have been shown to reduce the effectiveness of several approved antimalarial drugs. This phenomenon has become a new challenge to the malaria control and treatment sector. As a result, the goal of this study is to identify the best compound with the potential to be an antimalarial agent by employing a good model pharmacophore generated by mutated PfDHFR as a receptor. Using a computational chemistry method, a structurebased pharmacophore was utilized to analyze 165,878 compounds from the zinc database. Subsequently, these compounds were further examined by molecular docking. Furthermore, the ADMET properties, including absorption, distribution, metabolism, excretion, and toxicity, of these drug-candidates have been assessed. Furthermore, molecular dynamic simulations were employed to investigate the stability of the compound-receptor complex, while DFT investigations were utilized to examine the electronic characteristics of these compounds. Overall findings indicated that the substance C431 ZINC257280996 may be a potent PfDHFR-TS inhibitor due to its favorable binding energy of -42.26 kJmol, molecular dynamics simulations indication of its stability, and its advantageous pharmacokinetic characteristics along with its non-toxic nature. The findings suggested that compound C431 could be a promising antimalarial candidate. Furthermore, this research provides guidance for improving the structure of compound C431 for future synthesis and verifies its antimalarial efficacy in vitro.

 Genetic mutations in the dihydrofolate reductase-thymidylate synthase PfDHFR-TS enzyme of the malaria parasite Plasmodium falciparum have been shown to reduce the effectiveness of several approved antimalarial drugs. This phenomenon has become a new challenge to the malaria control and treatment sector. As a result, the goal of this study is to identify the best compound with the potential to be an antimalarial agent by employing a good model pharmacophore generated by mutated PfDHFR as a receptor. Using a computational chemistry method, a structurebased pharmacophore was utilized to analyze 165,878 compounds from the zinc database. Subsequently, these compounds were further examined by molecular docking. Furthermore, the ADMET properties, including absorption, distribution, metabolism, excretion, and toxicity, of these drug-candidates have been assessed. Furthermore, molecular dynamic simulations were employed to investigate the stability of the compound-receptor complex, while DFT investigations were utilized to examine the electronic characteristics of these compounds. Overall findings indicated that the substance C431 ZINC257280996 may be a potent PfDHFR-TS inhibitor due to its favorable binding energy of -42.26 kJmol, molecular dynamics simulations indication of its stability, and its advantageous pharmacokinetic characteristics along with its non-toxic nature. The findings suggested that compound C431 could be a promising antimalarial candidate. Furthermore, this research provides guidance for improving the structure of compound C431 for future synthesis and verifies its antimalarial efficacy in vitro.

 Genetic mutations in the dihydrofolate reductase-thymidylate synthase PfDHFR-TS enzyme of the malaria parasite Plasmodium falciparum have been shown to reduce the effectiveness of several approved antimalarial drugs. This phenomenon has become a new challenge to the malaria control and treatment sector. As a result, the goal of this study is to identify the best compound with the potential to be an antimalarial agent by employing a good model pharmacophore generated by mutated PfDHFR as a receptor. Using a computational chemistry method, a structurebased pharmacophore was utilized to analyze 165,878 compounds from the zinc database. Subsequently, these compounds were further examined by molecular docking. Furthermore, the ADMET properties, including absorption, distribution, metabolism, excretion, and toxicity, of these drug-candidates have been assessed. Furthermore, molecular dynamic simulations were employed to investigate the stability of the compound-receptor complex, while DFT investigations were utilized to examine the electronic characteristics of these compounds. Overall findings indicated that the substance C431 ZINC257280996 may be a potent PfDHFR-TS inhibitor due to its favorable binding energy of -42.26 kJmol, molecular dynamics simulations indication of its stability, and its advantageous pharmacokinetic characteristics along with its non-toxic nature. The findings suggested that compound C431 could be a promising antimalarial candidate. Furthermore, this research provides guidance for improving the structure of compound C431 for future synthesis and verifies its antimalarial efficacy in vitro.

 Genetic mutations in the dihydrofolate reductase-thymidylate synthase PfDHFR-TS enzyme of the malaria parasite Plasmodium falciparum have been shown to reduce the effectiveness of several approved antimalarial drugs. This phenomenon has become a new challenge to the malaria control and treatment sector. As a result, the goal of this study is to identify the best compound with the potential to be an antimalarial agent by employing a good model pharmacophore generated by mutated PfDHFR as a receptor. Using a computational chemistry method, a structurebased pharmacophore was utilized to analyze 165,878 compounds from the zinc database. Subsequently, these compounds were further examined by molecular docking. Furthermore, the ADMET properties, including absorption, distribution, metabolism, excretion, and toxicity, of these drug-candidates have been assessed. Furthermore, molecular dynamic simulations were employed to investigate the stability of the compound-receptor complex, while DFT investigations were utilized to examine the electronic characteristics of these compounds. Overall findings indicated that the substance C431 ZINC257280996 may be a potent PfDHFR-TS inhibitor due to its favorable binding energy of -42.26 kJmol, molecular dynamics simulations indication of its stability, and its advantageous pharmacokinetic characteristics along with its non-toxic nature. The findings suggested that compound C431 could be a promising antimalarial candidate. Furthermore, this research provides guidance for improving the structure of compound C431 for future synthesis and verifies its antimalarial efficacy in vitro.

Makale detayları

New inhibitor quadrupole mutant PfDHFR as antimalaria candidate: Structure-based pharmacophore, molecular docking, ADMET, molecular dynamic, and chemical quantum study

Yazarlar:

Putra Jiwamurwa Pama Tjitda | Febri Odel Nitbani

Yayıncı:

Marmara University

Ana Başlıklar:

Pharmacology and Pharmaceutical Sciences (Other)

Dergi:

Journal of Research in Pharmacy Vol.29 Issue 2, pp.790-805

Belge Tipi:

Makale

Yayın Tarihi:

8/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001341724

pISSN:

2630-6344

ADMET

DFT Study

Molecular Docking

Molecular Dynamic

Pharmacophore Modeling

Sayı

Makale detayları

New inhibitor quadrupole mutant PfDHFR as antimalaria candidate: Structure-based pharmacophore, molecular docking, ADMET, molecular dynamic, and chemical quantum study

Yazarlar: Putra Jiwamurwa Pama Tjitda | Febri Odel Nitbani

Yayıncı: Marmara University

Ana Başlıklar: Pharmacology and Pharmaceutical Sciences (Other)

Dergi: Journal of Research in Pharmacy Vol.29 Issue 2, pp.790-805

Belge Tipi: Makale

Yayın Tarihi: 8/2025

Belge Dili: İngilizce

Document ID (Org No.): 2001341724

pISSN: 2630-6344

ADMET

DFT Study

Molecular Docking

Molecular Dynamic

Pharmacophore Modeling

Sayı

Yazarlar:

Putra Jiwamurwa Pama Tjitda | Febri Odel Nitbani

Yayıncı:

Marmara University

Ana Başlıklar:

Pharmacology and Pharmaceutical Sciences (Other)

Dergi:

Journal of Research in Pharmacy Vol.29 Issue 2, pp.790-805

Belge Tipi:

Makale

Yayın Tarihi:

8/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001341724

pISSN:

2630-6344