RESUMEN

There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have implemented various computational drug design tools to go hand in hand with experiments for the design and discovery of potentially effective pyrazole-based therapeutics. This review highlights the milestones of pyrazole-containing inhibitors and the use of molecular modeling techniques in conjunction with experimental studies to provide a view of the binding mechanism of these compounds. The review focuses on the established targets that play a key role in cancer therapy, including proteins involved in tubulin polymerization, carbonic anhydrase and tyrosine kinase. Overall, using both experimental and computational methods in drug design represents a promising approach to cancer therapy.

Asunto(s)

Antineoplásicos , Neoplasias , Humanos , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Modelos Moleculares , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirazoles/química , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular

RESUMEN

Candida albicans infections and their resistance to clinically approved azole drugs are major concerns for human. The azole antifungal drugs inhibit the ergosterol synthesis by targeting lanosterol 14α-demethylase of cytochrome P450 family. The lack of high-resolution structural information of fungal pathogens has been a barrier for the design of modified azole drugs. Thus, a preliminary theoretical molecular dynamic study is carried out to develop and validate a simple homologous model using crystallographic structure of the lanosterol 14α-demethylase of Mycobacterium tuberculosis (PDB ID-1EA1) in which the active site residues are substituted with that of C. albicans (taxid 5476). Further, novel designed pyrazole analogs (SGS1-16) docked on chimeric 1EA1 and revealed that SGS-16 show good binding affinity through non-bonding interaction with the heme, which is different from the leading azole antifungals. The ADME-T results showed these analogs can be further explored in design of more safe and effective antifungal agents.

Asunto(s)

Inhibidores de 14 alfa Desmetilasa/química , Antifúngicos/química , Candida albicans/enzimología , Proteínas Fúngicas/química , Pirazoles/química , Proteínas Recombinantes de Fusión/química , Esterol 14-Desmetilasa/química , Inhibidores de 14 alfa Desmetilasa/síntesis química , Secuencia de Aminoácidos , Antifúngicos/síntesis química , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Candida albicans/química , Candida albicans/genética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Expresión Génica , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Pirazoles/síntesis química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Esterol 14-Desmetilasa/genética , Esterol 14-Desmetilasa/metabolismo , Homología Estructural de Proteína , Termodinámica