3DQSAR Approach Towards the Hydroxamic Acid Analogues as Matrix Metalloproteinase Inhibitors: A Key Role of Steric and Electrostatic Factors Using kNN MFA Method

Abstract: Matrix metalloproteinase-1 (MMP-1) plays a crucial role in cancer invasion and metastasis through extracellular matrix (ECM) degradation. Hydroxamic acids, known for their strong zinc-chelating ability, have emerged as potent MMP inhibitors with promising anticancer potential. However, optimizing their activity and selectivity remains a significant challenge.To address this, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed. This model was generated using stepwise variable selection k-nearest neighbor molecular field analysis (SW-kNNMFA), demonstrating robust internal (q2 = 0.7211) and external (pred_r2 = 0.6451) validation. The field plot derived from the developed SW-kNNMFA model indicates regions of positive electrostatic potential and positive steric potential.This suggests that, for the design of new, more active hydroxamic acid inhibitors of MMP-1, substituent groups should be less electronegative (favoring the positive electrostatic potential) and more bulky (favoring the positive steric potential) at their respective binding sites.