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Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives.

ABSTRACT: BACKGROUND:Pyrimidine is an important pharmacophore in the field of medicinal chemistry and exhibit a broad spectrum of biological potentials. A study was carried out to identify the target protein of potent bis-pyrimidine derivatives using reverse docking program. PharmMapper, a robust online tool was used for identifying the target proteins based on reverse pharmacophore mapping. The murine macrophage (RAW 264.7) and human embryonic kidney (HEK-293) cancer cell line used for selectivity and safety study. METHODS:An open web server PharmMapper was used to identify the possible target of the developed compounds through reverse pharmacophore mapping. The results were analyzed and validated through docking with Schrodinger v9.6 using 10 protein GTPase HRas selected as possible target. The docking studies with Schrödinger validated the binding behavior of bis-pyrimidine compounds within GTP binding pocket. MTT and sulforhodamine assay were used as antiproliferative activity. RESULTS AND DISCUSSION:The protein was found one of the top scored targets of the compound 18, hence, the GTPase HRas protein was found crucial to be targeted for competing cancer. Toxicity study demonstrated the significant selectivity of most active compounds, 12, 16 and 18 showed negligible cell toxicity at their IC50 concentration. CONCLUSION:From the results, we may conclude that GTPase HRas as a possible target of studied bis-pyrimidine derivatives where the retrieved information may be quite useful for rational drug designing.

SUBMITTER: Kumar S

PROVIDER: S-EPMC6768019 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives.

Kumar Sanjiv S Singh Jagbir J Narasimhan Balasubramanian B Shah Syed Adnan Ali SAA Lim Siong Meng SM Ramasamy Kalavathy K Mani Vasudevan V

Chemistry Central journal 20181022 1

<h4>Background</h4>Pyrimidine is an important pharmacophore in the field of medicinal chemistry and exhibit a broad spectrum of biological potentials. A study was carried out to identify the target protein of potent bis-pyrimidine derivatives using reverse docking program. PharmMapper, a robust online tool was used for identifying the target proteins based on reverse pharmacophore mapping. The murine macrophage (RAW 264.7) and human embryonic kidney (HEK-293) cancer cell line used for selectivit ...[more]

PMID: 30345469

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Project description:ObjectivesAntiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies.MethodsThree key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model.ResultsMutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition.ConclusionThis study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.

Dataset Information

Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives.

Publications

Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives.

Similar Datasets

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